tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and...
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Mutation Research, 154 (1985) 111-133 111 Elsevier
MTR 07193
Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984
John Ashby and C.R. Richardson Imperial Chemical Industries PLC, Central Toxicology Laboratory, Alderley Park, Cheshire (Great Britain)
(Received 27 December 1984) (Revision received 20 March 1985)
(Accepted 15 April 1985)
Summary
There is an increasing tendency to monitor human exposure to genotoxic chemicals by the assessment of chromosomal aberrations or sister-chromatid exchanges (SCEs) in peripheral blood lymphocytes. In order to assess the sensitivity of these techniques, and to discern minimal criteria for their conduct, a survey of 113 human lymphocyte cytogenetic surveillance studies conducted between 1965 and 1984 has been undertaken.
The present survey indicates the urgent need for standardization of study protocols. It is suggested that a common method of reporting chromosomal aberrations should be adopted, and that this should be based on the system described by Scott et al. It is also suggested that a minimum acceptable size of control and exposed populations should be agreed, and that potentially important factors such as the gender, the period and extent of exposure and individual smoking habits be defined in advance of the commission of future surveillance studies.
As general awareness of the ,possible hazard presented by exposure of man to genotoxic chemicals increases, so appropriate preventative industrial hygiene measures will be instituted. This implies that future human cytogenetic surveillance studies may yield either weakly positive or negative data. This emphasizes the current need for agreement on appropriate study protocols.
The formation of a central repository for control databases, and its subsequent updating and use by those involved in human cytogenetic surveillance studies, is recommended. Minimal experimental criteria for the design of future studies are also outlined.
There is an increasing tendency to monitor human exposure to genotoxic chemicals by the assessment of chromosomal aberrations or sister- chromatid exchanges (SCEs) in peripheral blood lymphocytes (Fig. 1). Use of the sister-chromatid exchange test protocol (SCE) as a possible surro- gate for the more resource-consuming chro- mosomal aberration assays is becoming more com- mon, but the implicit assumed equivalence of these two techniques requires further study.
Opinions differ as to the usefulness of cyto- genetic surveillance techniques. Purchase (1978) proposed that in cases where humans are working in the vicinity of an established mammalian genotoxin it would be prudent to limit exposure to a level that did not affect their normal chro- mosome morphology. The implication is that chemically induced increases in chromosomal aberrations might be taken as evidence of a possi- ble carcinogenic/mutagenic hazard to the exposed
0165-1110/85/$03.30 © 1985 Elsevier Science Publishers B.V. (Biomedical Division)
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112
" 0
t -
Q.
" 0 _= u)
25
20
15
10 !
5
0
l j
I I [ I [ t ~ I t I I I I I l L I I I L L
1965 1970 1975 1980 1985
Y e a r
Fig. 1. A plot of the number of h u m a n surveillance studies published between 1965 and 1984 as listed in Table 1.
population (Harnden, 1976). In contrast, a recent Gene-Tox review of cytogenetic assays (Preston et al., 1981) concluded that the observation of an increased incidence of chromosonal aberrations in the peripheral blood lymphocytes of populations exposed to xenobiotic chemicals provided only evidence of a clastogenic phenomenon. Recent discussion of the term genotoxin (Bridges, 1984) is timely, and it could be interpreted to encourage the concept that an assay for chromosomal aberra- tions can only yield clastogenicity data; however, the approach of Purchase and Harnden represents an acceptable compromise given the current state of uncertainty regarding the aetiology of environ- mentally associated human cancers and the as yet unrealized possibility crf chemically induced hu- man germ-cell mutations.
Of more immediate relevance is the scientific integrity and credibility of the average human surveillance cytogenetic study: an initial survey revealed such disparate study protocols and posi- tive study criteria that a more detailed review was undertaken. The present paper considers the data and conclusions drawn from 113 human surveil- lance studies published between 1965 and 1984.
The literature search was conducted using keywords *, therefore, not all published studies have been accessed; nonetheless, the majority of the relevant literature has been considered.
Discussion
The results of the 113 human surveillance stud- ies considered are displayed in Table 1. The infor- mation available for particular studies is often scanty, but the presentation of such inadequate data was considered necessary in order to present an accurate picture of the current status of this discipline. It is hoped that this compilation itself will prove instructive; the ensuing discussion is focussed on a few derived issues of current rele- vance.
Presentation of chromosomal aberration data in Ta- b& 1
Buckton and Pike (1964) and Savage (1976) have described systems for the categorization of chromosomal aberrations induced by radiation.
CLASSIFICATION OF C H R O M O S O M A L DAMAGE ACCORDING TO 8UCKTON AND PIKE
I . . . . A ..... I 1 TypeB ..... I
No abnormal i t ies apparen t chromat id gaps ch romat id b reaks isochromat id gaps
I
% AB(~ot) [+ / / gaps 1
] - not speci f ical ly c lassi f ied ch romosome b reaks chromat id in te rchanges J
I Type C ce l ls I
C~ C s (uns tab le ) ( s t ab le )
d lcent r i cs invers ions r ings t rans locat ions
acentr~c f ragments
I I I
%C(tod
I
Scheme 1. Classification of chromosomal aberrations as for- mulated by Buckton and Pike (1964). The addition of total aberrant cells as a percentage (% ABtot) is consistent with the recent UKEMS guidelines (Scott et al., 1983).
* The Chemical Abstracts and Science Citation Index com- puter files were searched for papers containing within their titles one word from each of the following two groups: lymphocyte, SCE, sister-chromatid, sister chromatid, chro- mosom, cytogene, mutagen, mutat and clastogen; clastogen, human, man, worker, occupation, industr, vivo, epidemiolog, study, studies and sureeill.
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The first is shown in Scheme 1 with the additional category of total aberrant cells (Tot Ab% + g) as recommended by the UKEMS subcommittee (Scott et al., 1983). Most investigators have adopted the system of Buckton and Pike for the classification of induced damage, although a few refer to brea- kage frequency which classifies dicentrics, etc. in terms of break-equivalents (Hirschorn and Cohen, 1968). Unfortunately, the detail in which the Buckton and Pike classification is employed varies considerably between studies. Some investigators list only breaks, or only C u or C s cells, or total C cells or only total aberrant cells etc. Further, whether or not gaps have been included is often unclear. When the present data were tabulated as reported by individual investigators few useful cor- relations were evident: We therefore re-analysed the aberration data reported, according to the clas- sification of Buckton and Pike, mindful of the recommendations of Scott et al. (1983). In some cases this was made difficult by the paucity of data presented, or by the fact that in a few in- stances we were working from preliminary com- munications or translations of somewhat obscure foreign publications. The classification of aberra- tions adopted in Table 1 is therfore an imperfect compromise, but had we adopted a particular for- mat (e.g. Scott et al., 1983), a significant propor- tion of the database would have had to be omitted. The present format enables data to be compared between studies and provides a mean value for the percentage of aberrant cells ( - g a p s ) across the control groups from 60 studies of 1.42 + 0.96%. This therefore provides an approximate historical value for the % frequency of aberrant cells in normal human lymphocytes. The corresponding value for SCEs across 47 of the present studies was 8.12 __+ 1.82 per cell. The central collection and collation of control data from all laboratories who routinely conduct these assays would provide an invaluable reference database. Further, general adoption of the standardized reporting format re- commended by the UK Environmental Mutagen Society (Scott et al., 1983; Scheme 1) should al- leviate many of the problems encountered in this survey.
General consideration of the database (Table 1) 42 discrete chemical environments are described
113
in Table 1, of these about 75% have at least one positive study associated with them. Most repeat studies are associated with exposure to vinyl chlo- ride, styrene, benzene and ethylene oxide. Each of these agents is clearly clastogenic to humans. Im- proved industrial hygiene measures have resulted in a decrease of vinyl-chloride-induced clastogenic- ity back to control levels in some studies; likewise, brief or low exposure to benzene appears to carry no clastogenic penalty. These and other studies have illustrated two uses of human cytogenetic studies to monitor the effect of changes in ex- posure pattern. The first concerns the decreasing clastogenic effect with increasing time since the last exposure to vinyl chloride or dimethylfor- mamide (see DMF in Table 1), and the second, the marked prophylactic effect of ascorbic acid on the clastogenicity of coal tar to exposed workers (see coal tar, Table 1). The clastogenicity of DMF to humans is very surprising given its experimental non-genotoxic status (de Serres and Ashby, 1981).
An interesting trend in Table 1 is that all of the established human carcinogens studied gave a positive response according to the authors' conclu- sions (vinyl chloride, asbestos, BCME, chromate handling, nickel refining, arsenic, benzene, ben- zidine derivatives, coal tar, y-radiation and the rubber industry). These positive observations focus the initial negative findings for several agents recently suspected of being possible human carcinogens, e.g. formaldehyde, acrylonitrile, epoxy resins and TCDD (all of these agents were re- garded as non-clastogenic in the studies conducted and are referred to by these names in Table 1). Equally, the clastogenic activity seen in individuals exposed to epichlorohydrin and styrene, for exam- ple, should act as the stimulus for continued cancer epidemiology studies.
Smoking appears to be a key-confounding fac- tor in human cytogenetic studies. Although no clear pattern emerges for the clastogenic conse- quences of this habit, the carcinogenic conse- quences are clear and it generally, but not always leads to an increase in SCEs. Smoking also ap- pears to have an enhancing effect on the clastogen- icity/SCE-inducing activity of some carcinogens, and this is consistent with current cancer epide- miology. By far the best study describing the SCE-inducing/enhancing effects of smoking is that
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TA
BL
E 1
AN
AL
YS
IS O
F
113
PU
BL
ISH
ED
PA
PE
RS
R
EL
AT
ING
TO
CH
EM
ICA
LL
Y
IND
UC
ED
CL
AS
TO
GE
NIC
CH
AN
GE
S
IN T
HE
L
YM
PH
OC
YT
ES
OF
M
AN
(s
ee
sepa
rate
ref
eren
ce l
ist)
.
Cat
egor
ies
of c
ytog
enet
ic d
amag
e ar
e de
scri
bed
in t
he t
ext
and
in
Sch
eme
1. s
, sm
oker
; ns
, n
on
-sm
ok
er;
E,
expo
sed
gro
up
. 5
cate
gori
es o
f co
ntro
l g
rou
p a
re u
sed:
MC
, m
atch
ed c
ontr
ol;
SC,
site
con
trol
; E
C,
exte
rnal
con
trol
; H
C,
hist
oric
al c
ontr
ol;
IC,
inte
rnal
(sa
me
per
son
pre
-ex
po
sure
) co
ntro
l. T
hes
e d
ata
wer
e re
-ana
lyse
d fr
om
the
or
igin
al a
ccor
ding
to
the
clas
sifi
cati
on o
f B
uckt
on a
nd P
ike
(196
4) a
s am
end
ed b
y S
cott
et
al.
(198
3).
The
pri
mar
y c
lass
ific
atio
ns o
f C
u an
d C
~ ce
lls
are
give
n w
here
ava
ilab
le,
toge
ther
wit
h th
e pe
rcen
tage
of
cell
s co
nta
inin
g a
ber
rati
on
s ( +
gap
s).
Fro
m t
hese
fig
ures
, ty
pe B
cel
ls (
chro
mat
id a
ber
rati
on
s) o
f th
e B
uckt
on a
nd
Pik
e cl
assi
fica
tion
can
be
deri
ved
by s
ubtr
acti
on.
The
inc
iden
ce o
f ch
rom
oso
mal
or
chro
mat
id g
aps
(g)
is u
ncle
ar i
n th
e re
po
rt o
f m
any
stu
dies
, co
nseq
uent
ly,
som
e of
the
Tot
AB
(%
) da
ta c
oncl
uded
in
Tab
le 1
may
be
inco
rrec
t as
we
assu
med
the
inc
lusi
on o
f ga
ps i
n ca
ses
whe
re t
he c
on
tro
l va
lues
for
tot
al a
ber
rati
on
s re
po
rted
see
med
hig
h w
ith
resp
ect
to t
he m
ajor
ity
of
the
data
base
. T
he m
ajor
ity
of t
he S
CE
dat
a ar
e pr
esen
ted
as t
he m
ean
val
ue +
_ S.D
. p
er c
ell.
In s
om
e ca
ses
thes
e w
ere
calc
ulat
ed f
rom
the
ind
ivid
ual
valu
es p
rese
nted
in
the
pape
r. O
n so
me
occa
sion
s a
rang
e is
giv
en b
ecau
se i
t w
as n
ot p
ossi
ble
to d
eriv
e a
mea
n v
alue
. R
efer
ence
s to
the
stu
dies
are
nu
mb
ered
chr
onol
ogic
ally
, b
ut
alph
abet
ical
wit
hin
each
yea
r (s
ee s
epar
ate
refe
renc
e li
st f
rom
tha
t us
ed w
ithi
n th
e te
xt).
Th
e 11
3 st
udie
s ar
e li
sted
alp
habe
tica
lly
by c
hem
ical
in
the
tabl
e, a
nd c
hron
olog
ical
ly w
ithi
n a
par
ticu
lar
chem
ical
en
vir
on
men
t. T
hus,
the
vin
yl c
hlor
ide
stud
ies
app
ear
tow
ard
s th
e en
d o
f th
e ta
ble
in t
he o
rder
in
whi
ch t
hey
wer
e pu
blis
hed.
Che
mic
al
Per
iod
of
Tim
e si
nce
Au
tho
rs'
Sm
oker
C
hro
mo
som
al a
ber
rati
on
s S
CE
s +
S.D
. R
ef.
expo
sure
ex
posu
re
conc
lusi
on
effe
ct
Gro
up
( N
)
C u
C
~ T
ot
Ab
T
ot
Ab
+ g
/c
ell
(%)
(%)
(%)
(%)
Acr
ylon
itri
le
15 y
r 0
- N
D
E
18
1.8
5.5
27
MC
18
2.
0 5.
1
Ars
enic
0-
22.5
yr
0 +
N
D
E
18
2.6
8.2
23
C
14
0.5
1.6
Asb
esto
s in
sula
tors
27
yr
0 +
+
E
(s)
15
10.5
1 _+
1.3
1 M
C(s
) 8
10.0
5 +
1.6
6 E
(ns)
10
9.
29 +
1.3
0 95
M
C(n
s)
6 7
.79
+ 1
.2
Asb
esto
s N
D
0 +
N
D
E
15
2.3
EC
15
1.
42
113
Bis
(chl
orom
ethy
l)et
her
2 yr
0
+
E
12
6.7
(BC
ME
) 3
w
+
ND
E
10
3.
1 19
C
?
2.0
BC
ME
(qu
otes
Zu
do
va
3 y
r 0
+
ND
E
53
4.
19
unpu
blis
hed)
C
77
2.
31
46
Ben
zene
1
-20
yr
3 y
r +
N
D
E
20
1.4
1.1
SC
5
0.6
0.4
1 E
C
? 0.
6 0.
8
Ben
zene
1
-18
yr
Var
ious
+
N
D
E
25
1.89
1.
22
2 M
C
25
0.49
0.
04
Ben
zene
1
-20
yr
1/2
yr
- N
D
E
9 2.
7 10
.5
± 1
.2
2-1
2 y
r 1
/2 y
r -
ND
E
7
3.4
9.6
+_0
.7
49
MC
7
2.5
11.4
+
1.1
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Ben
zene
spi
llag
e 7
h 3
m
- N
D
E
21
0.11
0.
32
2.01
6.
46
104
SC
20
0.
23
0.50
3.
05
5.43
Ben
zene
(0.
2-12
.4 p
pm
) 4
-18
yr
0 -
E
22
2.6
1.5
9.3
_+ 2
.9
112
MC
22
1.
9 1.
0 9.
6 _+
2.1
Ben
zidi
ne d
eriv
ativ
es
4-1
9 y
r 0
+
ND
E
?
3.34
64
C
?
0.26
Cad
miu
m/l
ead
/zin
c 3
-6 y
r 0
+
ND
E
24
0.
76
0.06
1.
35
5.00
11
C
15
0.
40
0 0.
47
3.17
Cad
miu
m
1-3
4 y
r 0
- N
D
E
40
0.56
0.
16
0.88
4.
94
SC
13
0.
80
0.02
0.
90
3.88
25
E
C
285
0.13
2.
18
Cad
miu
m
10 y
r 0
- N
D
E
14
1.5
4.0
87
C
14
1.3
3.6
Che
mic
al l
abo
rato
ry
ND
0
+
E
51
8.2
wor
kers
E
C
42
4.8
(als
o da
ta,
not
sho
wn
, N
D
0 +
+
E
(s)
17
18.4
fo
r ch
ildr
en o
f C
(s)
45
15.6
fe
mal
e w
orke
rs
ND
0
+
E(n
s)
17
19,9
C
(ns)
45
14
.0
41
Ch
loro
pre
ne
1-31
yr
0 +
N
D
E
? In
cr.
4 E
C
9 N
orm
al
Ch
loro
pre
ne
Ch
ron
ic
0 -
ND
E
?
No
inc
r 53
C
?
No
rmal
Ch
loro
pre
ne
ND
0
-11
m
+
ND
E
?
5.8
65
C
? 1.
6
Ch
rom
ium
tri
oxid
e 6
yr
0 +
+
E
12
0.
6 2.
2 3.
4 8.
08 +
2.7
78
(C
rO3)
(F
acto
ry I
II)
MC
14
0.
1 0.
8 1.
7 6.
6 +
0.8
Ch
rom
ium
trio
xide
1
-18
yr
0 +
N
D
E
12
5.48
-11.
13
79
(CrO
3)
SC
10
5.
09-7
.36
Cr/
Ni
plat
ing
ND
0
+
ND
E
?
Incr
In
cr
86
C
? N
orm
al
No
rmal
Cr/
Ni
plat
ing
ND
0
+
+
E
? In
cr r
elat
ed t
o u
rin
ary
Cr
Incr
97
C
?
No
rmal
N
orm
al
Cr/
Ni
wel
ders
3
m
3 m
-
ND
E
19
7 0.
10
0 0.
27
1.71
37
IC
19
7 0.
16
0 0.
25
1.67
Sta
inle
ss s
teel
0
+
E(s
) 9
2.1
3.1
10.8
+
0.6
W
elde
rs
4-3
0 y
r +
M
C(s
) 10
1.
2 1.
9 10
.5
+0
.3
74
Cr/
Ni
wel
ders
0
- E
(ns)
12
1.
1 1.
7 8.
2 _+
0.2
MC
(ns)
9
1.3
2.4
8.9
_+0.
4
Sta
inle
ss s
teel
wel
ders
19
yr
0 -
ND
E
24
2.
3 4.
1 11
.0
93
(Cr/
Ni)
M
C
24
2.6
4.6
12.0
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TA
BL
E 1
(co
ntin
ued)
,.~
Che
mic
al
Per
iod
of
Tim
e si
nce
Au
tho
rs'
Sm
ok
er
Ch
rom
oso
mal
ab
erra
tio
ns
SC
Es
+ S
.D.
Ref
.
exp
osu
re
exp
osu
re
conc
lusi
on
effe
ct
Gro
up
(N
) C
u
C~
Tot
Ab
T
ot
Ab
+ g
/c
ell
(%)
(%)
(%)
(%)
E(
- A
A)
35
5.07
E
( +
AA
) 35
1.
77
Coa
l ta
r w
orke
rs a
lso
Pro
ph
y-
expo
sed
to a
scor
bic
ND
5
m
lact
ic
100
acid
(A
A)
( +
AA
) ef
fect
se
en
MC
( -
AA
) 20
1.
50
MC
(+A
A)
20
1.45
Cok
e-ov
en e
mis
sion
s 30
yr
0 +
N
S
E
12
7.9
+ 1
1.2
94
MC
12
6.
7 __
_ 10.
6
Cyt
osta
tic
dru
g
ND
0
+
+
E(s
) 5
33.3
+
2.5
41
(c
ance
r pa
tien
ts;
IC(s
) 8
17.4
+
2.5
C
CN
U)
(+ s
mok
ing)
0
+
+
E(n
s)
5 35
.8
+ 7
.7
IC(n
s)
12
13.8
+
2.4
Cyt
osta
tic
dru
gs
Var
ious
0
+
ND
E
10
0.
8 19
.3
5.5
-10
.2
66
SC
10
0.
3 9.
6 4.
5 -7
.9
Cyt
osta
tic
drug
2
d 0
+
ND
E
8
11.5
-2
9.9
71
(T
reos
ulfa
n; 2
day
s)
IC
8 4.
6
DD
T
1-1
0 y
r 0
+
ND
E
25
20
.5
10
(ins
ecti
cide
) C
20
14
.1
2,4-
Dic
hlor
ophe
noxy
0
-4 m
0
-4 m
-
+
E
50
Onl
y ef
fect
ac
etic
aci
d (2
4D)
of s
mo
kin
g
77
C
? se
en
Die
sel
2-3
6 y
r 0
+
E(s
) 5
0.6
1.0
3.2
fum
es
+
MC
(s)
5 0.
2 1.
2 3.
8 61
( +
sm
okin
g)
0 -
E(n
s)
9 0
0.2
0.8
MC
(ns)
10
0
0.4
2.2
Dim
eth
ylf
orm
amid
e N
D
4" m
+
E
28
3.
82
(DM
F)
ND
6
m
+
ND
E
43
2.
74
57
ND
12
m
- N
D
E
49
1.59
C
21
1.
61
ED
TA
+p
esti
cid
es+
5
yr
0 -
+
E(s
) 10
8.
4 +
1.3
ta
nn
ing
age
nts
EC
(s)
11
9.1
+1
.3
88
E(n
s)
12
7.4
+0
.8
EC
(ns)
9
7.9
_.+ 1
.4
Epi
chlo
rohy
drin
0
SC
35
0.
46
1.42
1.
80
1 yr
0
+
ND
E
33
0.
87
1.91
2.
81
17
2 y
r +
E
31
1.
35
2.96
4.
00
![Page 7: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984](https://reader035.vdocument.in/reader035/viewer/2022080400/575070c91a28ab0f07d68ca0/html5/thumbnails/7.jpg)
Ep
ich
loro
hy
dri
n
ND
0
+
ND
E
93
1.
21
4.25
32
M
C
75
0.60
2.
38
Ep
ich
loro
hy
dri
n
4 yr
0
+
ND
E
28
3.
12
MC
34
2
.06
47
EC
21
1.
33
Ep
ich
loro
hy
dri
n
6 m
0
- N
D
E
33
2.00
10
1 (0
.4 m
g/m
3)
MC
25
1.
68
Ep
ox
y r
esin
s 3
-10
yr
0 -
ND
E
18
1.
2 2.
3 9.
0 43
(h
igh
an
d l
ow
MW
) M
C
18
1.9
2.9
8.7
Eth
yle
ne
ox
ide
ND
0
+
+
E(s
) 3
21.1
+
6.9
E
(ns)
2
16
.l
+_5
.7
41
C(n
s)
45
14.0
+
3.0
Eth
yle
ne
ox
ide
1-8
yr
0 +
?
E1
12
6.2
11.2
1
-3 y
r E
2 6
8.2
13.8
63
M
C
11
5.8
8.5
Eth
yle
ne
ox
ide
(Pla
nt
III)
V
arie
d
0-6
m
+
ND
H
igh
E
2 1
.45
-2.0
35
L
ow
E
24
1.1
-0.8
9
15
75
SC
21
0
.7-0
.5
8 -
11
Eth
yle
ne
ox
ide
Var
ied
0
+
ND
E
25
13
.02
+ 2
.3
76
C
10
7.86
+ 0
.5
Eth
yle
ne
ox
ide
0-3
yr
+
E
10
11.5
8 +
2.2
9 3
-6y
r 0
+
ND
E
5
13.0
6_+
2.07
91
6-1
0 y
r +
E
10
14
.45
+ 2
.21
0 S
C
10
7.86
_+ 0
.48
Eth
yle
ne
ox
ide
N D
0
- N
D
E
14
7.6
105
( <
5 p
pm
) M
C
14
7.98
Eth
yle
ne
ox
ide
5.7
yr
0 +
-
E(s
) 15
13
.49
+_ 2
.36
ster
iliz
er
C(s
) 7
8.24
_+ 0
.85
109
E(n
s)
10
12.3
1 _+
2.1
C(n
s)
15
7.52
_+0.
82
Fo
rmal
deh
yd
e 28
yr
0 -
- E
15
1.
67
3.07
72
M
C
15
1.07
3.
33
"r-R
adia
tion
~92
1r
ND
0
+
ND
E
10
7 In
cr
C
? N
orm
al
96
-f-R
adia
tio
n
N D
0
- N
D
E
? N
orm
10
2 C
?
No
rm
![Page 8: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984](https://reader035.vdocument.in/reader035/viewer/2022080400/575070c91a28ab0f07d68ca0/html5/thumbnails/8.jpg)
TA
BL
E 1
(co
nti
nu
ed
Ch
emic
al
Per
iod
of
Tim
e si
nce
Au
tho
rs'
Sm
ok
er
exp
osu
re
exp
osu
re
con
clu
sio
n
effe
ct
Ch
rom
oso
mal
ab
erra
tio
ns
Gro
up
(
N )
C
u
C~
To
t A
b
To
t A
b +
g
(%)
(%)
(%)
(%)
SC
Es_
+ S
,D.
/ce
ll
Ref
.
Inse
ctic
ide
and
S
pra
yer
0
+
ND
E
1 16
1.
24
5.43
her
bic
ide
E2
26
0.28
1.
80
spra
yin
g
IC
16
1.24
3.
76
No
n-
6 m
-
ND
E
1 in
sect
16
6.
24
9.24
spra
yer
E
2 h
erb
26
7.
24
12.7
6
IC
16
1.76
4.
52
Irid
ium
, se
e "r
-rad
iati
on
Lea
d (
man
ufa
ctu
re)
ND
0
- N
D
E
29
0.33
2.
1 3.
03
lnto
x
3 1.
2 3.
3 3
C
20
0.30
1.
9 3.
3
Lea
d (
ship
yar
d)
1-4
3 y
r 0
- N
D
E
35
0.49
0.
23
0.86
5.
46
SC
31
0.
37
0.06
0.
39
4.61
6
EC
28
5 0.
35
0.51
1.
25
3.35
Lea
d
< I
0 y
r +
E
?
incr
>1
0y
r 0
+
ND
E
?
> i
ncr
15
0 C
?
No
rmal
Lea
d (
smel
tin
g)
1-3
0 y
r 0
+
E
16
1.06
1.
06
14.1
6
(han
dli
ng
) 1
-3 y
r 0
+
ND
E
7
0.82
1.
03
3.78
16
C
20
0.50
0.
50
2.53
Lea
d (
smel
tin
g)
ND
0
+
ND
E
6
5.0
2.53
24
C
15
0.
4 1.
4
Lea
d (
smel
tin
g)
ND
0
+
+
E
18
4.1
Incr
58
M
C
12
2.3
No
rmal
Lea
d (
smel
tin
g)
ND
0
+
+
E
18
3.8
4.1
11.4
+
0.4
59
M
C
12
2.0
2.4
9.8
_+0.
3
Lea
d e
xp
ose
d c
hil
dre
n
ND
0
- N
D
E
19
8.42
85
(0
.4 ,
ttg
/ml
urin
e;
SC
12
8.
65
con
tro
l 0.
16
~g
/ml
urin
e)
Lea
d
> 2
yr
E
5 9.
57
0 U
ncl
ear
N D
S
C
5 10
.45
89
4 m
E
13
8.
67
SC
13
8.
50
Mer
cury
2
-11
yr
0 -
Hig
h E
4
0.25
1.
0 3.
76
Lo
w E
24
1.
38
1.92
4.
79
33
SC
8
2.47
3.
49
8.28
E
C
12
1.40
2.
32
3.86
![Page 9: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984](https://reader035.vdocument.in/reader035/viewer/2022080400/575070c91a28ab0f07d68ca0/html5/thumbnails/9.jpg)
Mer
cury
vap
ou
r (m
ean
5
-7 y
r 0
- N
D
E
12
0.5
0 0.
5 1.
5 11
0 3
#g
/ml
in b
lood
, C
15
0.
2 0
0.2
1.3
cont
rols
0.6
#g
/ml)
Nic
kel
refi
nery
21
yr
+
Hig
h E
9
0.9
12.8
4
.4-5
.2
(NiO
/Ni3
S2
) 25
yr
0 (g
aps)
N
D
Lo
w E
10
1.
3 19
.6
4.4-
5.3
80
21 y
r S
C
7 0.
6 4.
3 4
.4-6
.3
Nic
kel
plat
ing,
see
Cr/
Ni
plat
ing
Nic
kel
wel
ding
, see
Cr/
Ni
wel
ding
Org
ano
ph
osp
ho
rus
4 h
2 m
+
N
D
E
20
9.2
+0
.2
108
inse
ctic
ide
C
10
8.5
+0
.2
(exp
osed
fir
emen
)
Pai
nt i
ndus
try
1-4
3 y
r 0
- -
E
5 (S
CE
]7)
1.6
3.37
5.
57
8.87
39
(t
olu
ene/
xy
len
e)
MC
5
(SC
EI
7)
0.8
3.67
6.
27
8.83
Pen
tach
loro
phen
ol
4-3
0 y
r 0
+
+
E(s
) 22
0.
73
1.09
3.
29
9.4
-+ 1
.6
C(s
) 9
0.27
0.
52
2.56
8.
9 -+
1.2
70
C
(ns)
13
7.
6 -+
0.9
Pen
tach
loro
phen
ol
ND
0
+
+
E
22
lncr
N
orm
al
98
Na
salt
C
22
N
orm
al
No
rmal
Pet
role
um w
orke
rs
ND
0
+
ND
E
?
incr
36
C
?
No
rmal
Pet
role
um w
orke
rs
> 1
0 yr
0
+
- E
22
1
/2 >
10.
6 38
C
18
8.
74
Pet
role
um
Var
ious
0
+
E(s
) 6
3.6
8.3
10.9
w
orke
rs
+
MC
(s)
6 3.
4 7.
7 8.
6 73
0
- E
(ns)
6
1.4
4.5
7.6
MC
(ns)
6
1.4
4.4
7.3
Pet
role
um '
tan
k'
clea
ners
1
-20
yr
0 +
+
E
8
4.12
S
C
6 2.
5 56
E
C
10
2.16
Phe
noxy
-aci
d he
rbic
ide
4 m
0
- +
E
(s)
16
9.9
± 1
.2
spra
yers
IC
(s)
16
9.7
-+ 1
.7
92
E(n
s)
19
8.8
-+1.
5 IC
(ns)
19
8.
6 -+
1.1
Ru
bb
er i
ndus
try
ND
N
D
+
ND
E
9
lncr
68
Ru
bb
er i
ndus
try
ND
0
+
ND
E
?
lncr
81
C
?
No
rmal
xt~
![Page 10: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984](https://reader035.vdocument.in/reader035/viewer/2022080400/575070c91a28ab0f07d68ca0/html5/thumbnails/10.jpg)
TA
BL
E 1
(co
nti
nu
ed)
Ch
emic
al
Per
iod
of
Tim
e si
nce
Au
tho
rs'
Sm
ok
er
Ch
rom
oso
mal
ab
erra
tio
ns
SC
Es
+ S
.D.
Ref
.
exp
osu
re
exp
osu
re
con
clu
sio
n
effe
ct
Gro
up
( N
)
C u
C
~ T
ot
Ab
T
ot
Ab
+ g
/c
ell
Ru
bb
er w
ork
ers
5 yr
0
- -
E(s
) 14
3.
1 4.
7 13
.1
_+0.
5
C(s
) 5
4.8
5.9
11.0
5 _+
0.6
99
8
yr
- -
E(n
s)
14
2.6
3.8
11.2
+
0.3
C(n
s)
12
2.4
3.4
10.4
+
0.3
Ru
bb
er w
ork
ers
7.4
yr
0 -
+
E(s
) 31
1.
4 0.
3 4.
2 6.
0 13
.0
+0
.3
EC
(s)
14
0.9
0.3
5.2
6.6
12.2
-+
0.4
111
E(n
s)
24
1.2
0.5
3.1
4.9
11.0
-+
0.3
EC
(ns)
21
0.
7 0.
4 2.
9 4.
0 10
.5
_+0.
2
Sty
ren
e 1
-8.5
yr
0 +
N
D
E
10
16.3
16
.6
18
EC
5
1.6
1.8
Sty
ren
e 21
yr
0 +
N
D
E
5 1.
6 3.
8 20
E
C
20
2.1
5.5
Sty
ren
e 1
-15
yr
0 +
(
- )
E
16
15.1
5.
3 ±
1.0
C
6 2.
0 4.
4 +
0.6
22
1
yr
+ (
- )
E 10
16
.2
C
Sty
ren
e 0
.5-1
0 y
r 0
+
ND
E
6
6.83
8.
67
29
MC
6
2.6
7
4.50
Sty
ren
e 1
-15
yr
0 +
N
D
E
10
16.3
16
.6
31
MC
5
1.6
1.8
Sty
ren
e 5
yr
0 +
N
D
E
36
4.3
7.9
12.3
MC
37
1.
9 3.
2 6.
7 35
5
yr
0 +
N
D
E
20
6.2
-10
.6
MC
21
5.
4 -9
.6
Sty
ren
e 4
-27
yr
0 -
ND
E
24
1.
9 5.
1 48
M
C
24
1.5
3.8
Sty
ren
e; r
e-an
aly
sis
4-2
7 y
r 0
+ ?
N
D
E
24
7.0
62
of
ref.
48
C
24
5.3
Sty
ren
e N
D
0 -
ND
E
7
3.6
6.7
+ 0
.8
MC
8
2.9
7.6
+ 1
.2
67
ND
0
- N
D
E
9 3.
3 7.
8 -+
1.6
MC
5
3.6
7.6
_+ 1
.2
Sty
ren
e (3
-400
N
D
0 +
N
E
in
cr
lncr
(h
igh
)
mg
/m 3
) ex
po
sure
) 83
MC
n
orm
al
No
rmal
![Page 11: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984](https://reader035.vdocument.in/reader035/viewer/2022080400/575070c91a28ab0f07d68ca0/html5/thumbnails/11.jpg)
Sty
rene
(P
lant
VI)
1
-22
yr
0 +
N
D
E
7 1.
76
44.0
15
.14
+ 0
.46
84
C
4 0.
15
4.5
9.7
2+
1.4
8
Sty
rene
(13
pp
m)
8 y
r 0
+
ND
E
38
0.
43
(Mic
ronu
clei
) 90
C
20
0.
37
Sty
rene
30
yr
0 +
+
E
(s)
10
1.31
5.
87
9.63
C
(s)
3 1.
00
4.67
8.
37
103
E(n
s)
8 0.
87
7.25
7.
87
C(n
s)
3 1.
13
4.70
8.
56
Sty
rene
(m
ean
ND
0
- +
E
(s)
7 1.
6 18
.1
6.7
13.2
pp
m)
(exc
l. ga
p)
EC
(s)
5 2.
0 14
.3
7.3
106
E(n
s)
11
0.8
23.2
6.
5 E
C(n
s)
4 1.
3 15
.3
5.6
Sty
rene
8
yr
0 -
+
E
38
1.95
3.
50
107
C
20
1.85
3.
65
(cf.
90)
Sul
phit
e (w
ood
pu
lp)
15 y
r 0
+
+
E
7 1.
6 3.
7 7.
5 44
C
15
0.
1 0.
6 2.
7
TC
DD
A
cute
N
D
- N
D
Acu
te
45
No
inc
r (S
eves
o)
and
C
hro
nic
45
N
o i
ncr
60
chro
nic
C
45
No
rmal
Tet
rach
loro
ethy
lene
1
-18
yr
0 -
ND
E
7
2.5
8.7
+1
.0
40
MC
6
1.7
8.0
_+ 1
.1
To
luen
e 8
yr
0 +
E
(s)
10
1.0
1.9
9.1
19 y
r 0
+
E(s
) 8
2.5
3.1
9.6
0 +
C
(s)
11
1.8
3.1
9.7
42 /
8
yr
0 -
E(n
s)
3 1.
0 2.
3 7.
9 51
19
yr
0 -
E(n
s)
11
1.4
2.5
7.5
0 C
(ns)
4
1.3
2.3
8.0
Tol
uene
16
0
+
E(s
) 12
0.
42
1.13
0 3.
61
10.3
+
0.5
+
M
C(n
s)
9 0.
20
0.57
2.
19
8.9
+0
.4
69
+
E(s
) 8
0.38
0.
79
3.16
8.
5 +
0.3
M
C(n
s)
35
0.34
0.
49
2.68
7.
7 +
0.2
Tol
uene
N
D
0 +
+
E
20
in
cr
Incr
82
S
C
24
No
rmal
N
orm
al
Tri
chlo
roet
hyle
ne
ND
0
+
ND
E
6
9.7
+3
.2
55
C
11
7.9
+2
.9
Tri
chlo
roet
hyle
ne
ND
0
+
ND
E
6
9.04
+ 4
.9
54
C
? 7.
9 +
2.9
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TA
BL
E 1
(co
nti
nu
ed)
Ch
emic
al
Per
iod
of
Tim
e si
nce
Au
tho
rs"
Sm
ok
er
Ch
rom
oso
mal
ab
erra
tio
ns
SCE
s_+
S.D
. R
ef.
exp
osu
re
exp
osu
re
con
clu
sio
n
effe
ct
Gro
up
(
N )
C
u
C,
To
t A
b
To
t A
b +
g
/cel
l
(%)
(%)
(%)
(%)
Vin
yl c
hlo
rid
e 9
-29
yr
0 +
N
D
E
7 5.
54
0.69
9.
52
15.9
3 9
SC
3
1.41
0
1.94
3.
53
Vin
yl c
hlo
rid
e 4
-28
yr
0 +
N
D
E
11
1.55
3.
36
10.5
4 8
EC
10
0.
30
2.90
7.
60
Vin
yl c
hlo
rid
e 0
.5-1
2 y
r 0
+
ND
E
45
1.
56
10.3
1
SC
44
0.
56
6.67
14
EC
49
0.
35
5.90
Vin
yl
chlo
rid
e 10
.7 y
r 0
+
ND
E
56
1.
37
0.33
7.
96
SC
19
0.
53
1.10
4.
23
13
EC
5
0.50
0
3.10
Vin
yl
chlo
rid
e 1
.5-2
8 y
r 0
+
ND
E
37
2.
76
12
EC
12
1.
62
Vin
yl c
hlo
rid
e 10
.7 y
r 0
+
+
Hig
h E
17
1.
82
0.47
3.
18
8.88
26
C
24
0.
50
0.08
1.
08
3.79
Vin
yl c
hlo
rid
e -2
5 y
r 0
+
ND
H
igh
E
35
3.41
C
16
1.79
21
2.
5 y
r -
ND
E
16
2.
6 7.
6
MC
16
2.
3 7.
5
Vin
yl c
hlo
rid
e -2
5 y
r 2.
5 yr
-
ND
E
16
7.
6
MC
16
7.
5 28
HC
5
8.3
Vin
yl c
hlo
rid
e 1
0-2
7 y
r 0
+
- E
9
3.2
5.2
13.8
+
1.1
3 30
M
C
8 1.
0 1.
8 9.
41 +
__ 0.
4
Vin
yl c
hlo
rid
e 2
yr
0 -
ND
E
31
1.
60
(co
ntr
oll
ed 1
0 m
g/m
3
SC
35
1.
12
45
from
sta
rt o
f E
xpt.
) 3
yr
0 -
ND
E
31
1.
05
SC
35
n
ot
do
ne
Vin
yl c
hlo
rid
e 19
74
0 +
N
D
E
21
1.81
0.
43
2.90
10
.1
C
6 0.
50
0 1.
33
3.67
19
76
0 +
N
D
E
21
1.76
0.
86
5.05
14
.34
7.96
34
/
imp
rov
ed h
yg
ien
e)
C
6 0.
50
0 1.
17
4.85
6.
68
50
( -
5 p
pm
) 19
78
0 -
+ /
-
? E
23
0.
35
0 0.
57
3.83
C
8 0.
13
0 0.
38
1.15
Vin
yl c
hlo
rid
e lo
ng
0
+
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E
25
7.
31 +
_ 0.6
2 52
te
rm
C
? 6.
03 _
+ 0.2
8
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Wel
ding
, see
Cr/
Ni
wel
ding
ZIN
EB
(fu
ngic
ide)
N
D
0 +
ND
E
C
? 5.
98
? 1.
00
7
Ref
eren
ces
to T
able
1
1965
1 T
ough
, I.M
., an
d W
.M.
Cou
rt-B
row
n (1
965)
Chr
omos
ome
aber
rati
ons
and
expo
sure
to
ambi
ent
benz
ene,
Lan
cet,
1,68
4.
1971
2 Fo
rni,
A.M
., A
. C
appe
llin
i, E
. Pa
cifi
co a
nd E
.C.
Vig
lian
i (1
971)
Chr
omos
ome
chan
ges
and
thei
r ev
olut
ion
in s
ubje
cts
wit
h pa
st e
xpos
ures
to
benz
ene,
Arc
h.
Env
iron
. H
ealt
h, 2
3, 3
85-3
91.
1972
3 Sc
hmid
, E
., M
. B
auch
inge
r, S
. Pi
etru
ck a
nd G
. H
all
(197
2) C
ytog
enet
ic a
ctio
n of
lea
d in
hum
an p
erip
hera
l ly
mph
ocyt
es i
n vi
tro
and
in v
ivo,
Mut
atio
n R
es.,
16, 4
01-4
06.
1973
4 K
atas
ova,
L
.D.
(197
3) C
ytog
enet
ic a
naly
sis
of p
erip
hera
l bl
ood
of w
orke
rs
enga
ged
in t
he p
rodu
ctio
n of
chl
orop
rene
, G
ig.
Tr.
Pro
f. Z
abol
., 17
, 30
-33.
5
Yod
er,
J.,
M.
Wat
son
and
M.M
. B
enso
n (1
973)
L
ymph
ocyt
e ch
rom
osom
e an
alys
is o
f ag
ricu
ltur
al
wor
kers
du
ring
ex
tens
ive
occu
pati
onal
ex
posu
re
to
pest
icid
es,
Mut
atio
n R
es.,
21,
335-
340.
1974
60
'Rio
rdan
, M
.L.,
and
H.J
. E
vans
(19
74)
Abs
ence
of
sign
ific
ant
chro
mos
ome
dam
age
in m
ales
occ
upat
iona
lly
expo
sed
to l
ead,
Nat
ure
(Lon
don)
, 24
7, 5
0-53
. 7
Pili
nska
ja,
M.A
. (1
974)
Res
ults
of
cyto
gene
tic
exam
inat
ion
of p
erso
ns o
ccup
a-
tion
ally
con
tact
ed w
ith
fung
icid
e Z
ineb
, G
enet
ika,
5,
140-
146.
1975
8 D
ucat
man
, A
., K
. H
irsc
hhor
n an
d l.J
. Se
liko
ff (
1975
) V
inyl
chl
orid
e ex
posu
re
arid
hum
an c
hrom
osom
e ab
erra
tion
s, M
utat
ion
Res
., 31
, 16
3-16
8.
9 Fu
nes-
Cra
viot
o, F
., B
. Lam
bert
, J.
Lun
dste
n, L
. E
hren
berg
, A.T
. N
atar
ajan
and
S.
Ost
erm
an-G
olka
r (1
975)
C
hrom
osom
e ab
erra
tion
s in
wor
kers
exp
osed
to
vi
nyl c
hlor
ide,
Lan
cet,
1,4
59.
10 R
abel
lo,
M.N
., W
. B
ecak
, W
.F.
de A
lmei
da,
P. P
igat
i, M
.T.
Ung
aro,
T.
Mur
ata
and
C.A
.B.
Pere
ira
(197
5) C
ytog
enet
ic s
tudy
on
in
divi
dual
s oc
cupa
tion
ally
ex
pose
d to
DD
T,
Mut
atio
n R
es.,
28,
449-
454.
1976
11
Bau
chin
ger,
M.,
E.
Schm
id,
H.J
. E
inbr
odt
and
J. D
resp
(19
76)
Chr
omos
ome
aber
rati
ons
in l
ymph
ocyt
es a
fter
occ
upat
iona
l ex
posu
re t
o le
ad a
nd c
adm
ium
, M
utat
ion
Res
., 40
, 57
-62.
12
F
omen
ko,
V.N
., L
.D.
Kat
osov
a an
d G
.I.
Pav
lenk
o (1
976)
Cyt
ogen
etic
ana
lysi
s of
ly
mph
ocyt
es
from
th
e pe
riph
eral
bl
ood
of
oper
ativ
es e
ngag
ed
in
viny
l ch
lori
de p
olym
eris
atio
n, G
ig.
Tr.
Pro
f. Z
abol
., 9,
48-
50.
13
Purc
hase
, I.
F.H
., C
.R.
Ric
hard
son
and
D. A
nder
son
(197
6) C
hrom
osom
al e
ffec
t in
per
iphe
ral
lym
phoc
ytes
, Pr
oc.
Roy
. So
c. M
ed.,
69,
290-
291.
14
Sze
ntes
i, 1.
, E
. H
orny
ak,
G.
Ung
vary
, A
. C
zeiz
el,
Z.
Bog
nar
and
M.
Tim
ar
(197
6) H
igh
rate
of
chro
mos
omal
abe
rrat
ions
in
PVC
wor
kers
, M
utat
ion
Res
., 37
, 31
3-31
6.
19
77
15 C
alug
ar,
A.,
and
G.
Sand
ules
cu (
1977
) In
vest
igat
ions
on
chro
mos
omal
abe
rra-
ti
ons
in s
ubje
cts
expo
sed
to l
ead
in
thei
r oc
cupa
tion
, R
ev.
Med
.-C
hir.
, 81
, 87
-92.
16 D
eknu
dt,
G.H
., Y
. M
anue
l an
d G
.B.
Ger
gber
(19
77)
Chr
omos
omal
abe
rrat
ions
in
w
orke
rs
prof
essi
onal
ly e
xpos
ed
to
lead
, J.
T
oxic
ol.
Env
iron
. H
ealt
h,
3,
885-
891.
17 K
ucer
ovh,
M.,
V.S
. Z
hurk
ov,
Z.
Poli
vkov
a an
d J.
E.
lvan
ova
(197
7) M
utag
enic
af
fect
of
epic
hlor
ohyd
rin,
II.
Ana
lysi
s of
chr
omos
omal
abe
rrat
ions
in
lym
pho-
cy
tes
of p
erso
ns o
ccup
atio
nall
y ex
pose
d to
epi
chlo
rhyd
rin,
Mut
atio
n R
es.,
48,
355-
360.
18 M
eret
oja,
T
., H
. V
aini
o,
M.
Sor
sa
and
H.
Har
kone
n (1
977)
O
ccup
atio
nal
styr
ene
expo
sure
and
chr
omos
omal
abe
rrat
ions
, M
utat
ion
Res
., 56
, 19
3-19
7.
19 Z
udov
a, Z
., an
d K
. L
anda
(19
77)
Gen
etic
ris
k of
occ
upat
iona
l ex
posu
re t
o ha
loet
hers
, M
utat
ion
Res
., 46
, 24
2-24
3.
1978
20
Flei
g,
I., a
nd A
.M.
Thi
ess
(197
8) M
utag
enic
ity
stud
y of
wor
kers
em
ploy
ed i
n th
e st
yren
e an
d po
lyst
yren
e pr
oces
sing
and
man
ufac
turi
ng i
ndus
try,
Sca
nd.
J.
Wor
k E
nvir
on.
Hea
lth,
4,
254-
258.
21
H
anst
een,
I.L
., L
. H
ille
stad
, E
. Thi
is-E
vens
en a
nd S
.S. H
ilda
as (
1978
) E
ffec
ts o
f vi
nyl
chlo
ride
in
man
--
A c
ytog
enet
ic f
ollo
w-u
p st
udy,
Mut
atio
n R
es.,
51,
271-
278.
22
Mer
etoj
a,
T.,
H.
Jarv
enta
us,
M.
Sors
a an
d H
. V
aini
o (1
978)
1Sh
rom
osom
e ab
erra
tion
s in
ly
mph
ocyt
es o
f w
orke
rs e
xpos
ed
to s
tyre
ne,
Scan
d. J
. W
ork
Env
iron
. H
ealt
h, 4
, 25
9-26
4.
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TA
BL
E 1
(co
ntin
ued)
23
Nor
dens
on,
1.,
G.
Bec
kman
, L
. B
eckm
an a
nd S
. N
ords
trom
(19
78)
Occ
upa-
tio
nal
and
envi
ronm
enta
l ris
k in
and
aro
und
a sm
elte
r in
Nor
ther
n Sw
eden
, II
. C
hrom
osom
al A
berr
atio
ns in
wor
kers
exp
osed
to a
rsen
ic,
Her
edit
as,
88,
47-5
0.
24 N
orde
nson
, I.
, G
. B
eckm
an,
L.
Bec
kman
an
d S.
Nor
dstr
om (
1978
) O
ccup
a-
tiona
l an
d en
viro
nmen
tal r
isk
in a
nd a
roun
d a
smel
ter
in N
orth
ern
Swed
en,
IV.
Chr
omos
omal
abe
rrat
ions
in
wor
kers
exp
osed
to
lead
, H
ered
itas
, 88
, 26
3-26
7.
25 O
'Rio
rdan
, M
.L.,
E.G
. H
ughe
s an
d H
.J.
Eva
ns (
1978
) C
hrom
osom
e st
udie
s on
bl
ood
lym
phoc
ytes
of
men
occ
upat
iona
lly
expo
sed
to c
adm
ium
, M
utat
ion
Res
.,
58,
305-
311.
26
Pu
rcha
se,
I.F
.H.,
C.R
. R
icha
rdso
n, D
. A
nder
son,
G.M
. P
addl
e an
d W
.G.F
. A
dam
s (1
978)
Chr
omos
omal
ana
lysi
s in
vin
yl c
hlor
ide
expo
sed
wor
kers
, M
uta-
tion
Res
., 57
, 32
5-33
4.
27 T
hies
s, A
.M.,
and
F.
Flei
g (1
978)
Ana
lysi
s of
chr
omos
omes
of
wor
kers
exp
osed
to
acr
ylon
itrile
, A
rch.
Tox
icol
., 41
, 14
9-15
2.
1979
28
H
anst
ee n,
1.
L.
(197
9)
A
follo
w-u
p st
udy
of
PVC
w
orke
rs
two
year
s af
ter
expo
sure
, Pr
elim
inar
y re
sult
s us
ing
sist
er-c
hrom
atid
exc
hang
e fr
eque
ncy
as a
n as
say
of g
enet
ic d
amag
e, in
: G
enet
ic D
amag
e in
Man
Cau
sed
by E
nvir
onm
enta
l A
gent
s, A
cade
mic
Pre
ss,
New
Yor
k, p
p. 2
79-2
85.
29
Hoe
gste
dt,
B.,
K.
Hed
ner,
E.
Mar
k-V
ende
l, F
. M
itel
man
, A
. S
chue
tz a
nd S
. Sk
erfv
ing
(197
9) I
ncre
ased
fre
quen
cy o
f ch
rom
osom
e ab
erra
tion
s in
wor
kers
ex
pose
d to
sty
rene
, Sc
and.
J.
Wor
k E
nvir
on.
Hea
lth,
5,
333-
335.
30
K
ucer
ova,
M.,
Z.
Poliv
kova
and
J.
Bat
ora
(197
9) C
ompa
rati
ve e
valu
atio
n of
the
fr
eque
ncy
of c
hrom
osom
al a
berr
atio
ns a
nd
the
SC
E n
umbe
rs i
n pe
riph
eral
ly
mph
ocyt
es
of w
orke
rs
occu
pati
onal
ly e
xpos
ed t
o vi
nyl
chlo
ride
mon
omer
, M
utat
ion
Res
., 67
, 97
-100
. 31
M
eret
oja,
T.,
and
H.
Vai
nio
(197
9) T
he u
se o
f hu
man
lym
phoc
yte
test
s in
the
ev
alua
tion
of p
oten
tial
mut
agen
s: C
last
ogen
ic
activ
ity
of s
tyre
ne i
n oc
cupa
- tio
nal
expo
sure
, in
: G
enet
ic D
amag
e in
Man
cau
sed
by E
nvir
onm
enta
l A
gent
s,
Aca
dem
ic P
ress
, N
ew Y
ork,
pp.
213
-225
. 32
Pic
cian
o,
D.
(197
9) C
ytog
enet
ic i
nves
tigat
ion
of
occu
pati
onal
ex
posu
re
to
epic
hlor
hydr
in,
Mut
atio
n R
es.,
66,
169-
173.
33
Ver
scha
eve,
L.,
J.P.
Tas
sign
on,
M.
Lef
evre
, P.
de
Sto
op a
nd C
. S
usan
ne (
1979
) C
ytog
enet
ic i
nves
tigat
ion
on l
euko
cyte
s of
wor
kers
exp
osed
to m
etal
lic
mer
cury
, E
nvir
on.
Mut
agen
., 1,
259-
268.
1980
34
And
erso
n, D
., C
.R.
Ric
hard
son,
T.M
. W
eigh
t, I.
F.H
. P
urch
ase
and
W.G
.F.
Ada
ms
(198
0) C
hrom
osom
al a
naly
sis
in v
inyl
chl
orid
e ex
pose
d w
orke
rs,
Res
ults
fr
om a
naly
sis
18 a
nd 4
2 m
onth
s af
ter
an i
nitia
l sa
mpl
ing,
Mut
atio
n R
es.,
79,
151-
162.
35
And
erss
on,
H.C
., E
.A.
Tra
nber
g, A
.H.
Ugg
la a
nd G
. Z
ette
rber
g (1
980)
Chr
o-
mos
omal
ab
erra
tion
s an
d si
ster
-chr
omat
id e
xcha
nges
in
lym
phoc
ytes
of
men
oc
cupa
tiona
lly
expo
sed
to s
tyre
ne i
n a
plas
tic-
boat
fac
tory
, M
utat
ion
Res
., 73
, 38
7-40
1.
36 B
atik
yan,
G.G
., G
.S.
Shir
inya
n an
d R
.M.
Aru
tyun
yan
(198
0) S
iste
r ch
rom
atid
ex
chan
ge in
pet
role
um i
ndus
try
wor
kers
, B
iol.
Zh.
Arm
., 3
3, 7
53-7
55.
37
Blo
om,
A.D
., G
. Se
wel
l, S.
Ner
iishi
, Z
. P
yatt
, K
. O
hki,
D.
Pate
l, J.
Bea
ird,
D.
Cam
pos,
R
.B.
Ser
ra
and
D.
Cal
afio
re (
1980
) C
hrom
osom
al
abno
rmal
itie
s am
ong
wel
der
trai
nees
, E
nvir
on.
Int.
, 3,
459
-464
. 38
Car
rano
, A
.V.,
L.B
. Har
riso
n, B
.H.
May
all,
J.L
. M
inkl
er a
nd F
. C
ohen
(19
80)
Sist
er
chro
mat
id
exch
ange
stu
d;,e
s in
pe
trol
eum
ref
iner
y w
orke
rs,
Env
iron
.
Mut
agen
., 2,
263
. 39
Hag
lund
, U
., 1.
Lun
dber
g an
d L
. Z
ech
(198
0) C
hrom
osom
e ab
erra
tion
s an
d si
ster
chr
omat
id e
xcha
nges
in
swed
ish
pain
t in
dust
ry w
orke
rs,
Scan
d. J
. W
ork
Env
iron
. H
ealt
h, 6
, 29
1-29
8.
40
Iked
a, M
., A
. K
oizu
mi,
T.
Wat
anab
e, A
. E
ndo
and
K.
Sat
o (1
980)
Cyt
ogen
etic
an
d cy
toki
neti
c in
vest
igat
ions
on
lym
phoc
ytes
fro
m w
orke
rs o
ccup
atio
nall
y ex
pose
d to
tet
rach
loro
ethy
lene
, Tox
icol
. L
ett.,
5,
251-
256.
41
L
ambe
rt,
B.,
and
A.
Lin
dbla
nd (
1980
) S
iste
r ch
rom
atid
exc
hang
e an
d ch
ro-
mos
ome
aber
rati
ons
in l
ymph
ocyt
es o
f la
bora
tory
per
sonn
el,
J. T
oxic
ol.
En-
viro
n. H
ealt
h, 6
, 12
37-1
243.
42
M
aki-
Paa
kkan
en,
J.,
K.
Hus
gafv
el-P
ursi
aine
n,
P.-L
. K
allio
mak
i, J.
Tuo
min
en
and
M.
Sor
sa (
1980
) T
olue
ne-e
xpos
ed w
orke
rs a
nd c
hrom
osom
e ab
erra
tion
s, J
. T
oxic
ol.
Env
iron
. H
ealt
h, 6
, 77
5-78
1.
43
Mit
elm
an,
F.,
S. F
rege
rt,
K.
Hed
ner
and
K.
Hil
lber
tz-N
ilss
on (1
980)
Occ
upa-
ti
onal
exp
osur
e to
epo
xy r
esin
s ha
s no
cyt
ogen
etic
eff
ect,
Mut
atio
n R
es.,
77,
345-
348.
44
Nor
dens
on, 1
., G
. B
eckm
an,
L. B
eckm
an,
L.
Ros
enha
ll a
nd N
. S
tjer
nber
g (1
980)
Is
exp
osur
e to
sul
fur
diox
ide
clas
toge
nic?
C
hrom
osom
al a
berr
atio
ns a
mon
g w
orke
rs a
t a
sulf
ite
pulp
fac
tory
, H
ered
itas
, 93
, 16
1-16
4.
45
Roe
ssne
r, P
., R
.J.
Sram
, J.
Nov
akov
a an
d V
. L
ambl
(19
80)
Cyt
ogen
etic
ana
lysi
s in
wor
kers
occ
upat
iona
lly
expo
sed
to v
inyl
chl
orid
e, M
utat
ion
Res
., 73
, 425
-427
. 46
Sr
am,
R.J
., an
d N
.P.
Kul
esho
v (1
980)
Mon
itor
ing
the
occu
pati
onal
exp
osur
e to
m
utag
ens
by t
he c
ytog
enet
ic a
naly
sis
of h
uman
per
iphe
ral
lym
phoc
ytes
in v
ivo,
Arc
h. T
oxic
ol.,
Supp
l. 4,
11-
18.
47
Sram
, R
.J.,
Z.
Zud
ova
and
N.P
. K
ules
hov
(198
0) C
ytog
enet
ic a
naly
sis
of
peri
pher
al l
ymph
ocyt
es in
wor
kers
occ
upat
iona
lly
expo
sed
to e
pich
loro
hydr
in,
Mut
atio
n R
es.,
70,
115-
120.
48
Thi
ess,
A.M
., H
. Sc
hwel
ger
and
I. F
leig
(19
80)
Chr
omos
ome
inve
stig
atio
ns in
ly
mph
ocyt
es o
f w
orke
rs e
mpl
oyed
in
area
s in
whi
ch s
tyre
ne-c
onta
inin
g un
- sa
tura
ted
poly
este
r re
sins
are
man
ufac
ture
d, A
m.
J. I
nd.
Med
., 1,
205-
210.
49
Wat
anab
e, T
., A
. E
ndo,
Y.
Kat
o, S
. Sh
ima,
T.
Wat
anab
e an
d M
. Ik
eda
(198
0)
Cyt
ogen
etic
s an
d cy
toki
neti
cs o
f cu
ltur
ed l
ymph
ocyt
es f
rom
ben
zene
-exp
osed
w
orke
rs,
Int.
Arc
h. O
ccup
. E
nvir
on.
Hea
lth,
46,
31-
40.
1981
50
And
erso
n, D
., C
.R.
Ric
hard
son,
I.F
.H.
Purc
hase
, H
.J.
Eva
ns a
nd M
.L.
O'R
ior-
da
n (1
981)
Chr
omos
omal
ana
lysi
s in
vin
yl c
hlor
ide
expo
sed
wor
kers
: C
ompa
ri-
son
of t
he s
tand
ard
tech
niqu
e w
ith
the
sist
er c
hrom
atid
exc
hang
e te
chni
que,
M
utat
ion
Res
., 83
, 13
7-14
4.
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51
Don
ner,
M.,
K.
Hus
gafv
el-P
ursi
aine
n, J
. M
aki-
Paa
kkan
en,
M.
Sors
a an
d H
. V
aini
o (1
981)
Gen
etic
eff
ects
of
in-v
ivo
expo
sure
to
tolu
ene,
Mut
atio
n R
es.,
85,
293-
294.
52 G
eogi
eva,
V.,
and
M.
Tso
neva
(19
81)
Sist
er c
hrom
atid
exc
hang
es i
n pe
rson
s oc
cupa
tion
ally
exp
osed
to
viny
l ch
lori
de a
nd p
oly(
viny
l ch
lori
de),
Gen
et.
Sel.,
14
, 13
2-13
9.
53 G
u,
K.
(198
1)
Cyt
ogen
etic
eff
ect
of
chlo
ropr
ene
by
the
met
hod
of
sist
er
chro
mat
id e
xcha
nges
, S
hang
hai
Ti.
Hse
uoh.
Yua
n. H
seuh
. Pa
o.,
8, 1
73-1
76.
54 G
u, Z
.W.,
B. S
ele,
D.
Chm
ara,
P. J
albe
rt, M
. V
ince
nt, F
. V
ince
nt, C
. M
arka
and
J.
Fau
re (
1981
) E
ffec
ts o
f tr
ichl
oroe
thyl
ene
and
its
met
abol
ites
on
the
rate
of
sist
er c
hrom
atid
exc
hang
e, I
n vi
vo a
nd i
n vi
tro
stud
y on
hum
an l
ymph
ocyt
es,
Sem
. H
6p.,
57,
1511
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2.
55 G
u, Z
.W.,
B. S
ele,
P. J
albe
rt,
M. V
ince
nt, F
. V
ince
nt, C
. M
arka
, D
. C
hmar
a an
d J.
Fau
re (
1981
) In
duct
ion
of s
iste
r ch
rom
atid
exc
hang
e by
tri
chlo
roet
hyel
ene
and
its
met
abol
ite,
Tox
icol
. E
ur.
Res
., 3,
63-
67.
56 H
ogst
edt,
B
., B
. G
ullb
erg,
E.
Mar
k-V
ende
l, F
. M
itel
man
and
S.
Sk
erfv
ing
(198
1)
Mic
ronu
clei
and
chr
omos
ome
aber
rati
ons
in b
one
mar
row
cel
ls a
nd
lym
phoc
ytes
of
hum
ans
expo
sed
mai
nly
to p
etro
leum
vap
ours
, H
ered
itas
, 94
, 17
9-18
7.
57
Kou
dela
, K
., an
d K
. Sp
azia
(19
81)
Res
ults
of
cyto
gene
tic
exam
inat
ion
of
pers
ons
wor
king
in
an e
nvir
onm
ent
wit
h in
crea
sed
conc
entr
atio
n of
dim
ethy
l-
form
amid
e va
pors
in
the
atm
osph
ere,
Pra
c. L
ek.,
33,
121-
123.
58
M
aki-
Paa
kkan
en,
J.,
M.
Sors
a an
d H
. V
aini
o (1
981)
Chr
omos
ome
aber
rati
ons
and
SCE
s in
lea
d-ex
pose
d w
orke
rs,
Mut
atio
n R
es.,
85,
249.
59
Mak
i-P
aakk
anen
, J.
, M
. So
rsa
and
H.
Vai
nio
(198
1) C
hrom
osom
e ab
erra
tion
s an
d si
ster
chr
omat
id e
xcha
nges
in le
ad-e
xpos
ed w
orke
rs,
Her
edit
as, 9
4, 2
69-2
75.
60 M
ottu
ra,
A.,
G.
Zei
, F.
Nuz
zo,
C.
Cri
man
do,
R.
Gio
rgi,
P.
Ven
eron
i, L
. Pa
ggin
i, P.
Moc
arel
li,
M.,
Frac
caro
, B
. N
icol
etti
and
L.
De
Car
li (
1981
) E
valu
atio
n of
re
sult
s of
chr
omos
ome
anal
ysis
of
lym
phoc
ytes
of
TC
DD
-exp
osed
sub
ject
s af
ter
the
Seve
so a
ccid
ent,
Mut
atio
n R
es.,
85,
238.
61
Nor
dens
on,
I., A
. Sw
eins
, E
. D
ahlg
re n
and
L.
Bec
kman
(19
81)
A
stud
y of
ch
rom
osom
al a
berr
atio
ns in
min
ers
expo
sed
to d
iese
l ex
haus
ts,
Scan
d. J
. W
ork
Env
iron
. H
ealt
h, 7
, 14
-17.
62
Nor
pa,
H.,
H.
Vai
nio
and
M.
Sors
a (1
981)
C
hrom
osom
e ab
erra
tion
s in
ly
mph
ocyt
es o
f w
orke
rs e
xpos
ed t
o st
yren
e, A
m.
J. I
nd.
Med
., 2,
299
-304
. 63
Pe
ro,
R.W
., B
. Wid
egre
n, B
. H
oegs
tedt
and
F.
Mit
elm
an (
1981
) In
viv
o an
d in
vi
tro
ethy
lene
oxi
de e
xpos
ure
of h
uman
ly
mph
ocyt
es a
sses
sed
by c
hem
ical
st
imul
atio
n of
uns
ched
uled
DN
A s
ynth
esis
, M
utat
ion
Res
., 83
, 27
1-28
9.
64 Q
i, R
., S.
Z
hang
, H
. Y
an,
J.
Qi
and
L.
Li
(198
1)
Stud
ies
on
peri
pher
al
lym
phoc
yte
chro
mos
ome
chan
ges
in s
ubje
cts
expo
sed
to c
arci
noge
nic
arom
atic
am
ines
, Tia
njiu
Yiy
ao,
9, 6
84-6
85.
65
Sam
osh,
L.V
. (1
981)
C
hrom
osom
e ab
erra
tion
s in
lym
phoc
ytes
of
pers
ons
in
cont
act
wit
h po
lych
lorp
inen
e un
der
agri
cult
ure
cond
itio
ns,
Tsi
tol.
Gen
et.,
15,
62-6
7.
66 W
aksv
ik,
H.,
M.,
Boy
sen,
A
. B
roeg
ger
and
O.
Kle
pp
(198
1) C
hrom
osom
e ab
erra
tion
s an
d si
ster
chr
omat
id e
xcha
nges
in
pers
ons
occu
pati
onal
ly e
xpos
ed
to m
utag
ens/
carc
inog
ens,
Nat
o A
dv.
Inst
. Se
r. A
., 40
, 56
3-56
6.
67 W
atan
abe,
T.,
A.
End
o an
d K
. S
ato
(198
1) M
utag
enic
pot
enti
al o
f st
yren
e in
m
an,
Ind.
Hea
lth,
19,
37-
45.
1982
68 A
leks
andr
ov,
S.E
. (1
982)
F
requ
ency
of
chro
mos
omal
abe
rrat
ions
in
tire
and
ru
bber
ind
ustr
y w
orke
rs,
Gen
etik
a, 1
8, 1
61-1
63.
69 B
auch
inge
r, M
., E
. Sc
hmid
, J.
Dre
sp,
J. K
olin
-Ger
resh
eim
, R.
Hau
f an
d E
. Su
lir
(198
2) C
hrom
osom
e ch
ange
s in
lym
phoc
ytes
aft
er o
ccup
atio
nal
expo
sure
to
to
luen
e, M
utat
ion
Res
., 10
2, 4
29-4
35.
70 B
auch
inge
r, M
., J.
Dre
sp,
E.
Schm
id a
nd R
. H
auf
(198
2) C
hrom
osom
e ch
ange
s in
lym
phoc
ytes
aft
er o
ccup
atio
nal
expo
sure
to
pent
achl
orop
heno
l (P
CP)
, M
u-
tati
on R
es.,
102,
83-
88.
71 C
lare
, M
.G.,
W.G
. Jo
nes
and
J.H
. T
aylo
r (1
982)
Sis
ter
chro
mat
id-e
xcha
nges
in
hum
an l
ymph
ocyt
es e
xpos
ed t
o si
ngle
cyt
otox
ic d
rugs
in
vivo
ori
n v
itro
, E
ur.
J.
Can
cer
Cli
n. O
ncol
., 18
, 97
9-98
9.
72
Flei
g, I
., N
. Pe
tri,
W.G
. S
tock
er a
nd A
.M.
Thi
ess
(198
2) C
ytog
enet
ic a
naly
sis
of
bloo
d ly
mph
ocyt
es
of
wor
kers
ex
pose
d to
fo
rmal
dehy
de
in
form
alde
hyde
m
anuf
actu
ring
and
pro
cess
ing,
J.
Occ
up.
Med
., 24
, 10
09-1
012.
73
Fr
edga
, K
., L
. Dav
ring
, M
. S
unne
r, B
.O.
Ben
gtss
on, C
.-G
. E
lind
er,
P. S
igtr
yggs
- so
n an
d M
. B
erli
n (1
982)
Chr
omos
ome
chan
ges
in
wor
kers
(s
mok
ers
and
nons
mok
ers)
exp
osed
to
auto
mob
ile
fuel
s an
d ex
haus
t ga
ses,
Sc
and.
J.
Wor
k E
nvir
on.
Hea
lth,
8,
209-
221.
74
Hus
gafv
el,
K.,
P.L
. K
alli
oma
and
M.
Sors
a (1
982)
A c
hrom
osom
e st
udy
amon
g st
ainl
ess
stee
l w
elde
rs,
J. O
ccup
. M
ed.,
24,
762-
766.
75
Joh
nson
and
Joh
nson
(19
82)
Pre
lim
inar
y re
port
on
pilo
t re
sear
ch, C
hrom
osom
e st
udy
of w
orke
rs a
t si
tes
whe
re e
thyl
ene
oxid
e is
uti
lise
d as
a s
teri
lant
, 30
M
arch
: L
ette
r to
th
e D
irec
tor,
O
ccup
atio
nal
Safe
ty
and
Hea
lth,
D
ept.
of
L
abou
r, W
ashi
ngto
n, D
C.
76
Lau
rent
, C
., J.
Fre
deri
c an
d F.
Mar
echa
l (1
982)
Stu
dy o
f cy
toge
neti
c ef
fect
s in
et
hyle
ne o
xide
int
oxic
atio
n, C
.R.
Sra
nces
Soc
. B
iol.
Ses.
Fil.
, 17
6, 7
33-7
35.
77 L
inna
inm
aa,
K.,
and
H.
Vai
nio
(198
2) S
CE
s am
ong
herb
icid
e sp
raye
rs e
xpos
ed
to 2
,4-D
and
MC
PA
, in
: A
bstr
. 12
th A
nnu.
Mtg
. E
nvir
on.
Mut
agen
. So
c.,
Fin
land
, Ju
ne 1
982,
144
. 78
Sar
to,
F.,
I. G
omin
ato,
V.
Bia
nchi
and
A.G
. L
evis
(198
2) I
ncre
ased
inc
iden
ce o
f ch
rom
osom
al a
berr
atio
ns a
nd s
iste
r ch
rom
atid
exc
hang
es in
wor
kers
exp
osed
to
chro
mic
aci
d (C
r203
) in
ele
ctro
plat
ing
fact
orie
s, C
arci
noge
nesi
s, 3
, 10
11-1
016.
79
Ste
lla,
M.,
A.
Mon
tald
i, R
. R
ossi
, G
. R
ossi
and
A.G
. L
evis
(19
82)
Cla
stog
enic
ef
fect
s of
chr
omiu
m o
n hu
man
lym
phoc
ytes
in
vitr
o an
d in
viv
o, M
utat
ion
Res
., 10
1,15
1-16
4.
80 W
aksv
ik,
H.,
and
M.
Boy
sen
(198
2) C
ytog
enet
ic a
naly
ses
of l
ymph
ocyt
es f
rom
w
orke
rs i
n a
nick
el r
efin
ery,
Mut
atio
n R
es.,
103,
185
-190
.
1983
81
Ale
ksan
drov
, S.
E.,
and
V.S
. Z
hurk
ov (
1983
) C
hrom
osom
e ab
erra
tion
s in
the
ly
mph
ocyt
es o
f w
orke
rs i
n th
e ru
bber
ind
ustr
y, G
ig.
Tr.
Pro
f. Z
abol
., 5,
52-
53.
82 B
auch
inge
r, M
., E
. Sc
hmid
, J.
Dre
sp a
nd J
. K
olin
-Ger
resh
eim
(19
83)
Chr
o-
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TA
BL
E 1
(co
ntin
ued)
m
osom
e ao
erra
uons
ana
Sls
ter-
chro
mat
id e
xcha
nges
in t
olue
ne-e
xpos
ed w
orke
rs,
Mut
atio
n R
es.,
113,
231
-232
. 83
Cam
urri
, L
., S.
Cod
elup
pi a
nd C
. P
edro
ni (1
983)
Chr
omos
omal
abe
rrat
ions
and
si
ster
-chr
omat
id e
xcha
nges
in
styr
ene-
expo
sed
wor
kers
, M
utat
ion,
R
es.,
113,
23
8-23
9.
84 C
amur
ri,
L.,
S. C
odel
uppi
, C
. P
edro
ni a
nd L
. Sc
ardu
elli
(198
3) C
hrom
osom
al
aber
rati
ons
and
sist
er-c
hrom
atid
exc
hang
es
in
wor
kers
exp
osed
to
styr
ene,
M
utat
ion
Res
., 11
9, 3
61-3
69.
85
Dal
pra,
L.,
M.G
. T
ibile
tti,
G.
Noc
era,
P.
Giu
lott
o, L
. A
urit
i, V
. Car
nell
i an
d G
. Si
mon
i (1
983)
SC
E
anal
ysis
in
ch
ildr
en e
xpos
ed t
o le
ad
emis
sion
fro
m
a sm
eltin
g pl
ant,
Mut
atio
n R
es.,
120,
249
-256
. 86
Den
g, C
, B
. Ou,
J.
Hua
ng,
Z.
Zhu
o, H
. X
ian,
M.
Yao
, M
. C
hen,
Z.
Li,
S. S
heng
an
d Z
. Y
ei
(198
3) C
ytog
enet
ic e
ffec
ts i
n el
ectr
opla
ting
wor
kers
, H
uanj
ung
Kex
ue X
ueba
o, 3
, 26
7-27
1.
87 F
leig
, I.
, H
. R
ieth
, W
.G.
Stoc
ker
and
A.M
. T
hies
s (1
983)
Chr
omos
ome
inve
sti-
ga
tions
of
wor
kers
exp
osed
to
cadm
ium
in
the
man
ufac
turi
ng o
f ca
dmiu
m
stab
ilize
rs a
nd p
igm
ents
, Eco
toxi
col.
Env
iron
. Sa
f.,
7, 1
06-1
10.
88 G
onza
les,
C.M
., D
. L
oria
, R
. N
agel
and
E.
Mat
os (
1983
) G
enot
oxic
mon
itor
ing
of w
orke
rs o
f a
chem
ical
ind
ustr
y: s
iste
r chr
omat
id e
xcha
nge
and
Salm
onel
la-S
9 te
st,
J. E
xp.
Clin
. C
ance
r R
es.,
2, 4
15-4
19.
89 G
rand
jean
, P.
, H
.C.
Wul
f an
d E
. N
iebu
hr (
1983
) S
iste
r ch
rom
atid
exc
hang
e in
re
spon
se to
var
iati
ons
in o
ccup
atio
nal l
ead
expo
sure
, E
nvir
on. R
es.,
32, 1
99-2
04.
90
Hoe
gste
dt,
B.,
B.
Ake
sson
, K
. A
xell,
B.
Gul
lber
g,
F.
Mit
elm
an,
R.W
. Pe
ro,
S.
Sker
fvin
g an
d H
. W
elin
der
(198
3) I
ncre
ased
fre
quen
cy o
f ly
mph
ocyt
e m
icro
- nu
clei
in
wor
kers
pr
oduc
ing
rein
forc
ed p
olye
ster
res
in w
ith
low
exp
osur
e to
st
yren
e, S
cand
. J.
Wor
k E
nvir
on.
Hea
lth,
9,
241-
246.
91
L
aure
nt,
C.,
J.
Fre
deri
c an
d F
. M
arec
hal
(198
3) I
ncre
ased
sis
ter
chro
mat
id
exch
ange
fre
quen
cy i
n w
orke
rs e
xpos
ed t
o et
hyle
ne o
xide
, A
nn.
Gen
et.,
26,
13
8-14
2.
92
Lin
nain
maa
, K
. (1
983)
Sis
ter
chro
mat
id e
xcha
nges
am
ong
wor
kers
occ
upat
ion-
al
ly
expo
sure
d to
th
e ph
enox
y he
rbic
ides
2,
4-D
an
d M
CP
A,
Ter
atog
en.
Car
cino
gen.
Mut
agen
., 3,
269
-279
. 93
L
ittor
in,
M.,
B.
Hoe
gste
dt,
B.
Stro
emba
eck,
A
. K
arls
son,
H.
Wel
inde
r,
F.
Mite
lman
an
d S.
Ske
rfvi
ng (
1983
) N
o cy
toge
neti
c ef
fect
s in
lym
phoc
ytes
of
stai
nles
s st
eel
wel
ders
, Sc
and.
J.
Wor
k E
nvir
on.
Hea
lth,
9,
259-
264.
94
Min
er,
J.K
., W
.N.
Rom
, G
.K.
Liv
ings
ton
and
J.L
. L
yon
(198
3) L
ymph
ocyt
es
sist
er c
hrom
atid
exc
hang
e (S
CE
) fr
eque
ncie
s in
cok
e ov
en w
orke
rs,
J. O
ccup
. M
ed.,
25 3
0-33
. 95
R
om,
W.N
., G
.K.
Liv
ings
ton,
K.R
. C
asey
, S.
D.
Woo
d, M
.J.
Egg
er,
G.L
. C
hin
and
L.
Jero
min
ski
(198
3) S
iste
r ch
rom
atid
exc
hang
e fr
eque
ncy
in
asbe
stos
w
orke
rs,
J. N
atl.
Can
cer
Inst
., 70
. 45
-48.
96
Roz
gaj,
R.,
D.
Hor
vat,
J. R
acic
and
M.
Nov
akov
i (1
983)
Chr
omos
omal
abe
rra-
tio
ns i
n pe
rson
s oc
cupa
tion
ally
exp
osed
to
Irid
ium
-192
, M
utat
ion
Res
., 11
3,
301.
97
Sar
to,
F.,
I. C
omin
ato,
V.
Bia
nchi
and
A.G
. L
evis
(19
83)
Chr
omos
omal
dam
age
in w
orke
rs e
xpos
ed to
chr
omic
aci
d (C
rO3)
, M
utat
ion
Res
., 11
3, 3
03-3
04.
98 S
chm
id,
E.,
M.
Bau
chin
ger
and
J.
Dre
sp
(198
3) C
hrom
osom
e an
alys
es o
f w
orke
rs f
rom
a o
enta
chlo
roph
enol
pla
nt,
Mut
atio
n R
es.,
113,
304
-305
.
99 S
orsa
, M
., J.
M
aki-
Paa
kkan
en a
nd
H.
Vai
nio
(198
3) A
ch
rom
osom
e st
udy
amon
g w
orke
r gr
oups
in
the
rubb
er i
ndus
try,
Sca
nd.
J. W
ork
Env
iron
. H
ealt
h,
9, 4
3-47
. 10
0 Sr
am,
R.J
., L
. D
obia
s, A
. P
asto
rkov
a, P
. R
ossn
er a
nd L
. Ja
nca
(198
3) E
ffec
t of
asco
rbic
aci
d pr
ophy
laxi
s on
the
fre
quen
cy o
f ch
rom
osom
e ab
erra
tion
s in
the
pe
riph
eral
lym
phoc
ytes
of
coal
-tar
wor
kers
, M
utat
ion
Res
., 12
0, 1
81-1
86.
101
Sram
, R
.J.,
L.
Lan
da a
nd I
. Sa
mko
va (
1983
) E
ffec
t of
occu
pati
onal
exp
osur
e to
ep
ichl
oroh
ydri
n on
th
e fr
eque
ncy
of c
hrom
osom
e ab
erra
tion
s in
pe
riph
eral
ly
mph
ocyt
es, M
utat
ion
Res
., 12
2, 5
9-64
. 10
2 T
usch
l, H
., R
. K
ovac
and
H.
Alt
man
n (1
983)
UD
S a
nd S
CE
in
lym
phoc
ytes
of
pers
ons
occu
pati
onal
ly e
xpos
ed to
low
lev
els
of io
nizi
ng ra
diat
ion,
Hea
lth
Phys
.,
45,
1-7.
10
3 W
atan
abe,
T.,
A.
End
o, M
. K
umai
and
M.
Iked
a (1
983)
Chr
omos
ome
aber
ra-
tion
s an
d si
ster
chr
omat
id e
xcha
nges
in s
tyre
ne-e
xpos
ed w
orke
rs w
ith
refe
renc
e to
the
ir s
mok
ing
habi
ts,
Env
iron
. M
utag
en.,
5,
299-
309.
1984
10
4 C
lare
, M
.G.,
A
. Y
ardl
ey-J
ones
, A
.C.
Mac
lean
and
B
.J.
Dea
n (1
984)
Chr
o-
mos
ome
anal
ysis
fro
m p
erip
hera
l bl
ood
lym
phoc
ytes
of
wor
kers
aft
er a
n ac
ute
expo
sure
to
benz
ene,
Br.
J.
Ind.
Med
., 4
1,24
9-25
3.
105
Han
sen,
J.P
., J.
All
en,
K.
Bro
ck,
J. F
alco
ner,
M.J
. H
elm
s, G
.C.
Sha
ver
and
B.
Str
ohm
(19
84)
Nor
mal
sis
ter
chro
mat
id e
xcha
nge
leve
ls i
n ho
spit
al s
teri
liza
tion
em
ploy
ees
expo
sed
to e
thyl
ene
oxid
e, J
. O
ccup
. M
ed.,
26,
29-
32.
106
Han
stee
n, I
.-L
., O
. Je
lmer
t, T
. T
orgr
imse
n an
d B
. F
orsu
nd (
1984
) L
ow h
uman
ex
posu
re t
o st
yren
e in
rel
atio
n to
chr
omos
ome
brea
ks,
gaps
and
sis
ter
chro
- m
atid
exc
hang
es,
Her
edit
as,
100,
87-
91.
107
Hoe
gste
dt,
B.
(198
4) M
icro
nucl
ei
in l
ymph
ocyt
es w
ith
pres
erve
d cy
topl
asm
, A
m
etho
d fo
r as
sess
men
t of
cyt
ogen
etic
dam
age
in m
an,
Mut
atio
n, R
es.,
130.
63-7
2.
108
Lar
ripa
, I.
, E
. M
atos
, M
. L
abal
de
Vin
ness
a an
d S.
Bri
eux
de S
alum
(19
83)
Sist
er c
hrom
atid
exc
hang
es in
a h
uman
pop
ulat
ion
acci
dent
ally
exp
osed
to
an
orga
noph
osph
orus
pes
tici
de, R
ev.
Bra
sil.
Gen
et.,
6,
719-
727.
10
9 L
aure
nt,
C.,
J. F
rede
ric
and
A.Y
. L
eona
rd (
1984
) Si
ster
chr
omat
id e
xcha
nge
freq
uenc
y in
wor
kers
exp
osed
to
high
lev
els
of e
thyl
ene
oxid
e,
in a
hos
pita
l st
eril
izat
ion
serv
ice,
Int
. A
rch.
Occ
up.
Env
iron
. H
ealt
h, 5
4, 3
3-43
. 11
0 M
abill
e, V
., H
. R
oels
, P.
Jac
quet
, A
. L
eona
rd a
nd R
. L
auw
erys
(19
84)
Cyt
o-
gene
tic
exam
inat
ion
of l
euko
cyte
s of
wor
kers
exp
osed
to
mer
cury
vap
ors,
Int
. A
rch.
Occ
up.
Env
iron
. H
ealt
h, 5
3, 2
57-2
60.
111
Mak
i-P
aakk
anen
, J.,
M.
Sor
sa a
nd H
. V
aini
o (1
984)
Sis
ter
chro
mat
id e
xcha
nges
an
d ch
rom
osom
e ab
erra
tion
s in
rub
ber
wor
kers
, T
erat
ogen
. C
arci
noge
n. M
uta-
ge
n.,
4, 1
89-2
00.
112
Sart
o, F
., I.
Com
inat
o, A
.M.
Pin
ton,
P.G
. B
rove
dani
, E
. M
erle
r, M
. Pe
ruzz
i, V
. B
ianc
hi a
nd A
.G.
Lev
is (
1984
) A
cyt
ogen
etic
stu
dy o
n w
orke
rs e
xpos
ed t
o lo
w
conc
entr
atio
ns o
f be
nzen
e, C
arci
noge
nesi
s,
5, 8
27-8
32.
113
Srb,
V.,
E.
Kuc
ova
and
M.
Mus
il (1
984)
Tes
ting
gen
otox
ic a
ctiv
ity
in e
xpos
ure
to a
sbes
tos,
1.
Cyt
ogen
etic
exa
min
atio
n of
lym
phoc
ytes
of
hum
an p
erip
hera
l bl
ood,
Pra
c. L
ek.,
36,
175-
178.
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127
of Soper et al. (1984). Chromosomal gaps can occur at high inci-
dences, thus their inclusion or otherwise by inves- tigators can effect dramatically the total incidence of aberrations recorded. Unfortunately, however, many investigators either fail to record them or to make clear if they have or not. In Table 1 we have assumed the incorporation of gaps in several cases, e.g. in refs. 18 and 65, but have assumed their omission in other studies, e.g. in refs. 7 and 54. However, the criteria we adopted for these deci- sions would have led us to assume that the data in ref. 44 excluded gaps when in fact it included them. Caution is therefore indicated when using the data in Table 1 to discuss the effect of scoring for gaps. Some agents, e.g. nickel subsulphide, seem particularly prone to gap induction in the absence of chromosomal aberrations or SCEs (ref. 80 in Table 1).
Finally, an external historical control database for chromosomal aberrations and SCE is needed in order to check new studies. This would also help to refine assay endpoints. For example, con- cern must be expressed that in ref. 109 of Table 1, an increase in SCEs/cell from 8.5 to 9.2 was regarded as positive, while in ref. 110 an increase from 5.4 to 6.5 was regarded as negative. Again, the reader is referred to recent papers on this subject (Soper et al., 1984; Carrano and Moore, 1982). Similar concerns also apply to some of the chromosomal aberration data. For example, with the present mean value for the percentage of aber- rant cells [AbTot(% - g)] over 60 studies of 1.42 + 0.96 one must be concerned at why a correspond- ing control incidence of 5.8% aberrant cells should have been observed in the study described in ref. 63 of Table 1. Reference to historical control incidences can also sometimes prove an alert to simple printing errors, for example, the plus and minus gaps data shown in ref. 83 of Table 1 are obviously reversed--they have been changed in Table 1. The difference between intra- and inter- laboratory historical controls should not be ne- glected.
primary importance. The acquisition of these data is complicated by 3 major factors:
(i) The genetic event or change being monitored is usually already evident in control populations. For example, the level of chromosomal abnormali- ties or SCEs in the lymphocytes of any individual, although low, is always positive (Fig. 2). Likewise, the use of more empirical markers such as the mutagenicity of urine or the alkylation of macro- molecules has to be measured with respect to a background level that is seldom if ever zero. These background incidences impose the need for de- tailed control studies being conducted before any possible chemically induced changes can be de- termined with confidence. Such control studies are often inadequate and sometimes absent.
(ii) The background incidence of all genetic events varies with time and between individuals. Thus, it is not uncommon to find differences be- tween the control level of SCEs between repeat experiments to be of greater magnitude than that demonstrated between the exposed and the control group in some studies reported as positive. Such factors emphasize the importance of an adequate number of control observations and appropriate statistical techniques for data handling.
(iii) Based on the published literature it seems probable that some laboratories start to use cyto- genetic assays before an adequate intra-laboratory control database has been accumulated. This im- plies sole reliance by the investigators on concur- rent control values, or literature precedents, and in the usual case of weak 'chemically induced' changes this makes data analysis difficult. This problem is exacerbated by the inevitable refinement of assay techniques (which often lead to changes in control rates) and the non-uniform method of reporting data. Ultimately, the concurrent control group of a study assumes greatest importance; however, com- parison of such control groups with previous con- trol data from that laboratory, or with control data from other laboratories can provide a useful method of assessing the integrity of a particular study.
Definition of the normal (control) incidence of chro- mosomal aberrations
With any human surveillance technique, the accumulation of appropriate control data is of
Acquisition of appropriate control databases Table 1 reflects the fact that in most cases
control data have been acquired alongside test data, there being no generally accessible and agreed
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128
n = 6 0
~ i ~ i ~ ; ) t 1 ~ ` ~ ' ~ i i ~ i ~ L ~ L L i [ i ~ t l ' ~ i ~ ` [ ~ J ~ i 1 t ~ i ~ L ~ i ~ i ~ i i l t l t S t u d y
~ 1 ~ r ~ ' ~ r ~ r ~ 1 ~ I ~ 1 ~ [ ~ ' ~ 1 ~ I ~ 1 ~ r ~ i ~ 1 ~ 1 1 ~ 1 1 1 ~ ] ~ ' ~ r ~ ] : ~ I ~ [ ~ 1 ~ n u m b e r
t ~ = 4 7
Fig. 2. Plot of the control level of SCEs and total aberrant cells (%, - gaps) as listed in Table 1. Studies are arranged chronologically, i.e., in order of increasing ref. No. in Table 1. When the choice was available, data for non-smokers were selected. The meart values shown are presented numerically in the text.
database to which to refer. Of the 113 studies discussed, 50 had 12 or less control individuals and few had 20 or a greater number. The poss ible dangers of using small control groups, especial ly when reference to intra-laboratory historical con- trols is not possible, can be illustrated by selective re-analysis of data presented by Hogstedt et al. (1981). This study involved the surveil lance of a populat ion of 16 individuals exposed in various ways to petro leum vapour. Posit ive exposure-re- lated cytogenet ic effects were demonstrated in both the bone marrow and the peripheral l ymphocytes of both the high- and, the low-exposure groups. Reference to 16 control individuals was poss ible (see Table 1, ref. 56). The conclus ions of the study were wel l - founded, but in the fo l lowing analysis the intrinsic statistical problems posed by small studies is i l lustrated by our selective regrouping of the data presented. Our just i f icat ion for these manipulat ions of data is that many small surveil- lance studies are presented in Table 1, and in several cases equivocal conlus ions were drawn.
21
" " 1 6 . 8
0 0 . 12 .6 "1o
"~ 8 .4
4 . 2
Total database ( n = 2 6 )
9)
(10)
I I 1 (3 L H
Test groups
Fig. 3. The human bone marrow micronucleus assay data of Hogstedt et al. (1981) plotted as percentage of micronucleated PCEs for the control (C), low-exposure group (L) and the high-exposure group (H). The agent of exposure was mainly petroleum vapour and the data are discussed in the text. Numbers in brackets represent the individuals per group. Sig- nificance determined by Student's t test (2-sided; *P values; *0.05, **0.01, ***0.001. Bar lines represent the S.D. of the mean of individual observations.
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21 One person removed from each group (n --- 23) 21 'Worst case' selection of 6 per group
129
16.8
0. 12.6
"~ 8.4
0
~ 42
(9) I I I
C L H
Test groups Fig. 4. The data shown in Fig. 3 are replotted above with the omission of the most deviant result from each of the groups. See legend to Fig. 3. Significance determined by Student's t test (2-sided; *P values; *0.05, **0.01, ***0.001. Bar lines represent the S.D. of the mean of individual observations.
The data shown in Fig. 3 represent a graphical presentat ion of the positive response concluded by Hogstedt et al. based on the total numerical data presented for mic ronuc lea ted p o l y c h r o m a t i c erythrocytes (PCEs) in the bone mar row of the test groups. Fig. 4 shows the same data plotted with the omission of the most deviant result f rom each of the 2 exposed and the control groups. A much more convincing positive response is produced. Thus, 3 individuals out of 26 made the difference in confidence levels (S.D.s) evident between Figs. 3 and 4. However, neither the slope of the dose - response relationship, nor the qualitative ou tcome of the s tudy would have been changed by elimination of these 3 individuals.
The data shown in Figs. 5 and 6 represent the effect of splitting each of the 3 groups into 2 subgroups, and plott ing each to demonst ra te the theoretical max imum and min imum response that could have been deduced f rom this s tudy by the selection of 6 appropr ia te part icipants in each group f rom the pool of 26 people evaluated. Obvi- ously, the smaller a s tudy gets, the greater is the chance of unrepresentative individuals influencing the outcome of the s tudy (either way). The in- duced effect shown in Fig. 5 is statistically signifi- cant ( P > 0.001) and clearly positive, while that shown in Fig. 6 is clearly negative. These qualita-
(8)
--', 16.8
0 0- 12.6
o 8 .4
"~ 4.2
(6)
C k H
Test groups Fig. 5. The data shown in Fig. 3 are replotted above using the 6 control individuals with the lowest percentage of micro- nucleated PCEs and 6 individuals from the low- (L) and high- (H) exposure groups with the highest percentage of micro- nucleated PCE level. This response therefore represents the largest that could be derived from the total database (Fig. 3). Significance determined by Student's t tests (2-sided; *P val- ues; *0.05, **0.01, ***0.00l. Bar lines represent the S.D. of the mean individual observations.
tive fluctuations suggest that small groups of ex- posed individuals should be avoided in human surveillance studies.
The contrived statistical analysis undertaken above can be defended by consideration of the findings of one of the smaller studies shown in Table 1 (Gu et al., 1981). In that study exposure to trichloroethylene was reported to induce a signifi-
21 'Best case' selection of 6 per group
16.8
g~ 0 O. 12.6
t~ (9
8.4
~ 4.2
(6) I t ( 6 ~ / " / ' ~
I I I C L H
Test groups
(6)
Fig. 6. The data shown in Fig. 3 are replotted above using 6 individuals from each group to show the smallest change in micronucleated PCE levels (see legends to Figs. 3 and 5).
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1 3 0
cant increase in SCEs within the chromosomes of human peripheral lymphocytes (ref. 54 of Table 1). 6 exposed individuals were compared with an un- defined number of controls (probably 6 assuming equal numbers of metaphases analysed in test and control individuals). The response recorded for those exposed was presented as an average (9.045 +_ 4.898 SCEs/cell) and this was suggested to be significantly elevated as compared to the concur- rent control values of 7.910_+ 2.890 SCEs/cell. However, the SCE values presented for the ex- posed individuals varied between 6.67 and 10.97 per cell, while the 95% limits inferred from the S.D.s of the control values varied between 2.13 and 13.69 SCEs/cel l (Fig. 7). Therefore , the con- clusion drawn of a positive chemically induced effect seems insecurely based. Further, the statisti- cal significance attributed to these data by the authors was based largely upon the mean values derived from multiple sampling of each individual, rather than from the assessment of effects induced in a large group of exposed individuals. In a fundamental sense the conclusions drawn were therefore not supported by an appropriate statisti- cal treatment of the data.
Origin of variations in control levels Three sources of variation are apparent for
most methods of assaying human populations;
20
16
o 12
0 8
I
i l l i i l I I J Exposed Mean of Control Control
individuals test gp. (+SD, (+2SD) (±SD) (-J- SD n unknown)
of means)
Fig. 7. The data of Gu et al. (1981) are plotted showing the mean ± S.D. for repeat sampling of 6 individuals exposed to trichloroethylene, and the mean ( +_ S.D.) of these 6 means. The control data (± S.D. and +_ 2 S.D.) are shown and discussed in the text.
uncertainty associated with the extent and dura- tion of exposure to the xenobiotic chemical, indi- vidual sensitivity and protocol differences. Refer- ence to Table 1 shows that only broad generliza- tions are made by most authors with respect to exposure, and in many cases the issue is ignored completely. Some investigators present relatively detailed exposure data, but only a few assayed the population before exposure occurred. The second source of variability in assay data is that of natural biological variation. This is a problem particular to the use of small test groups and limited control data, and it has been discussed in detail by Car- rano and Moore (1982) and by Soper et al. (1984).
The third source of variability relates to dif- ferences in test protocol between individual inves- tigators. Reference to the SCE control data shown in Fig. 2 suggests significant inter-study variabil- ity. However, in one of the largest single studies undertaken to date, Soper et al. (1984) observed a remarkably stable control rate of SCEs among 479 individuals of 9.9 (range 5.0-17.5) which is close to the mean value for the 47 studies shown in Fig. 2 (8.12 +_ 1.82). Within this context the relatively large inter-study variations evident in Fig. 2 are probably associated more with small sample sizes than with protocol differences between investiga- tors. Soper et al. (1984) recently presented data that highlighted how different investigators can produce different conlusions from the same SCE slides, mean values of between 8.8 and 11.2 SCEs/cel l being recorded. Such data confirm the most fundamental of protocol requirements, namely, that rigid calibration criteria are required if more than one cytogeneticist is involved in the reading of a study. Clearly, the standardization of test protocols, the acquisition of an enlarged his- torical control database and the selection of larger test and concurrent control groups is to be encour- aged. A more demanding list of requirements has recently been delineated by Hook (1982) in an ICPEMC report, and by Carrano and Moore (1982).
Use of the SCE assay as a surrogate for chro- mosomal aberration assays
The relative ease of scoring SCE assays has led to their increasing use over the past few years in human surveillance studies. Carrano and Moore
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(1982) have outlined the implicit statistical limita- tion of this technique, but similar concerns may apply equally to human chromosomal aberration assays if appropriately assessed.
In the present survey about one third (35 of 113; 31%) of studies employed both the SCE and the chromosomal aberration techniques. In the majority of these a qualitatively similar conclusion was drawn, about half of them (14) produced double negative outcomes and about half (18) produced double positive effects. The possible ef- ficacy of the SCE assay as a surrogate for a full chromosomal aberration assay is therefore sup- ported by the present database. This issue is, how- ever, worthy of further evaluation and the exten- sive ethylene oxide study undertaken by Soper et al. (1984) and Stolley et al. (1984) will provide a firm foundation for these.
Potential sensitivity problems of future human lymphocyte eytogenetic studies
It becomes increasingly unlikely that new popu- lations of workers who have been exposed to sig- nificant levels of a genotoxin will be discerned. This is mainly because genotoxicity data now exist for most of the major environmental and in- dustrial chemicals. In the case of major synthetic genotoxins it is likely that improved hygiene mea- sures will have already been instituted before a surveillance study is mounted. Reference to the ethylene oxide and vinyl chloride data in Table 1 illustrates this point by the fact that the greatest cytogenetic damage was observed at the early stages of surveillance, subsequent responses having reduced roughly in proportion to the revised hy- giene measures instituted. This consideration sug- gests that when human populations are assayed for chemically induced chromosome damage (or other changes) following limited exposure to a known genotoxin, then effects will generally be weak. This in turn requires adequate foreknowledge of the sensitivity of the cytogenetic assay employed. Car- rano and Moore, for example, have suggested that the use of the SCE assay will be made difficult in such situations due to its insensitivity and inherent variability (Carrano and Moore, 1982). This is not a new problem -- it invariably happens that new genotoxicity assays are calibrated against the worst-case situation, and then, when employed
131
prospectively, yield equivocal data. Each human surveillance assay will probably
present its own unique sensitivity problems; and each of these will be dominated by the background level of the event or lesion being monitored and exacerbated by system-specific restraints. An ex- ample of the former is the presence of S-methyl- ated proteins in control populations which com- plicates interpretation of macromolecular methyl- ation studies (Ehrenberg and Osterman-Golkar, 1980; Bailey et al., 1981). An example of the latter is that human lymphocyte cytogenetic assays may not detect S-phase-specific clastogens due to ex- posure having taken place almost completely dur- ing the Go phase of the cell cycle. Nonetheless, the latter problem should not be invoked too easily to explain negative results in man. For example, for- maldehyde is reported to be non-clastogenic to exposed humans (Fleig et al., 1982; Table 1, ref. 72). However, the clastogenicity of formaldehyde is known not to be confined to S phase (Miretskaya and Shvartsman, 1982), thus, the significance of its inactivity in humans cannot be reduced on this count. In fact, the sensitivity of human lympho- cyte clastogenicity assays appears somewhat ex- traordinary given that many of the aberrations scored, including SCEs, are dependent upon chem- ical lesions being present on the genome during its replication. Wolff (1981) has suggested that the observation of SCEs in human lymphocytes ex- posed in vivo during the G o phase of the cell cycle, yet assessed at the subsequent metaphase in- stigated by treatment in vitro with mitogens such as PHA, is due to the failure of the cell to remove these lesions in the G0-G 1 phases of the cell cycle. It therefore seems probable that the apparent 'S- phase'-specific action of some clastogens may have little relevance of the interpretation of human clastogenicity data.
Genotoxic threshold dose levels Although not currently sustainable by data it
seems probable that organic genotoxic chemicals will have a dose level below which the risk implicit in exposure becomes negligibly small, or even zero. Clearly, if threshold values do exist, albeit they be different for individual chemicals, and variable among a given human population for each chem- ical, they should form an integral part of the risk
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estimation process. It is probably this belief that has given rise to the concept of genetically signifi- cant dose (GSD) referred to in a recent IPCEMC newsletter (1980) and the parallelogram concept of Sobels (1982). Although ill-defined at present, such concepts may have a critical role to play in the future. The particular danger is that a human threshold dose level may be defined by reference to negative cytogenetic data generated in a poorly designed study.
Relevance o f acute surveillance data to the eventual
induction o f cancer in man The opportunity now exists to probe the acute
consequences of exposure of man to chemicals already established as genotoxic: if cytogenetic effects are evident in exposed populations then it would seem prudent to assume that a possible mutagenic or carcinogenic hazard exists to those exposed. If such affects are absent, a genotoxic hazard may not exist, either because the chemical in question is only genotoxic in vitro or because the people exposed have been adequately pro- tected. These broad conclusions may prove to be wrong on occasion, the need at hand it to ensure that such errors are not due to faulty experimental conception, design, execution or statistical analy- sis.
Recommendations
Several recent reviews of epidemiologic and de- sign aspects of somatic chromosome breakage and sister-chromatid exchange studies have empha- sized the minimal criteria that should apply to study design and interpretation (Gebhart, 1982; Hook, 1982; Kucerov/t, 1982; Archer, 1984). In these reviews all of the relevant factors are dis- cussed in detail. Gebhart (1982) lists data for humans undergoing chemotherapy and from these analysies past criteria for study design become apparent, e.g., in 21% of studies no control group was included, 32% of studies had less than 10 exposed individuals, 11.5% of studies evaluated less than 50 cells per individual while 14% evaluated more than 100 cells. These trends are similar to those encountered in the present study. By far the most demanding criteria for study de- sign are those listed by Hook (1982). That article
suggests that the most important aspect of a study is the preparation undertaken before its commis- sion, e.g. the matching of controls, the documenta- tion of exposure and even the conduct of a limited study of those most heavily exposed to anticipate the likely outcome of the study. Within the context of such requirements most of the 113 studies re- viewed herein are seriously deficient on several counts.
The International Commission for Protection Against Environmental Mutagens and Carcino- gens (ICPEMC) has recently initiated a task group to list minimal design criteria for human surveil- lance studies. In the absence of knowlege of their deliberiations it would seem prudent to emphasize the following points for future surveillance studies:
(a) That the issues discussed by Hook (1982), Gebhart (1982) and Archer (1984) be considered in detail.
(b) That the commissioning laboratory should have an adequate historical control database and have adopted a standardized method of data re- porting and interpretation. The latter should be consistent with the recommendations of Scott et al. (1983).
(c) That particular attention should be given to the choice and matching of the test and control groups. Mindful of the issues discussed by Hook (1982) it is recommended that only in exceptional circumstances should a study be mounted where less than 25 exposed and 25 matched control individuals are available. Obviously, the weaker the anticipated response the greater will be the number of individuals required to demonstrate a significant effect. In this sense the recommenda- tion of Hook (1982) to mount a pilot study before the main study becomes of particular importance.
Acknowledgements
We are grateful to Stuart Kettle for conducting the literature search and wish to acknowledge the patient assistance of Sue Rodger, Jane Steele and Isabelle Naegelen.
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