tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and...

23
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) (Received27 December1984) (Revision received20 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 ElsevierSciencePublishers B.V. (BiomedicalDivision)

Upload: john-ashby

Post on 29-Aug-2016

213 views

Category:

Documents


0 download

TRANSCRIPT

Page 1: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984

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)

Page 2: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984

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.

Page 3: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984

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

Page 4: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984

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

Page 5: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984

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

Page 6: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984

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

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

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

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

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

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

Page 12: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984

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

+

ND

E

25

7.

31 +

_ 0.6

2 52

te

rm

C

? 6.

03 _

+ 0.2

8

Page 13: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984

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.

Page 14: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984

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.

Page 15: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984

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

-151

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-

Page 16: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984

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.

Page 17: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984

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

Page 18: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984

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.

Page 19: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984

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).

Page 20: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984

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

Page 21: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984

(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

Page 22: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984

132

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.

References

Archer, P.G. (1984) Some statistical and methodologic issues in cytogenetic testing, in: G.S. Omenn and H,V. Gelboin

Page 23: Tabulation and assessment of 113 human surveillance cytogenetic studies conducted between 1965 and 1984

(Eds.), Genetic Variability in Responses to Chemical Ex- posure, Banbury Report 16, Cold Spring Harbor Labora- tory, Cold Spring Harbor, NY, pp. 369-376.

Bailey, E., T.A. Connors, P.V. Falmer, S.M. Gorf and J. Richard (1981) Methylation of cysteine in haemaglobin following exposure to methylating agents, Cancer Res., 41, 2514-2517.

Bridges, B.A. (1984) Use of the terms mutagenicity and geno- toxicity, Mutation Res., 132, 139.

Buckton, K.E., and M.C. Pike (1964) Time in culture: An important variable in studying in vivo radiation induced chromosome damage in man, Int. J. Radiat. Biol., 8, 439-452.

Carrano, A.V., and D.H. Moore (1982) The rationale and methodology for quantifying sister chromatid exchange in humans, in: J.A. Heddle (Ed.), Mutagenicity - - New Hori- zons in Genetic Toxicology, Academic Press, New York, Ch. 10, pp. 267-299.

de Serres, F.J., and J. Ashby (Eds.) (1981) Evaluation of Short-Term Tests for Carcinogens: Results of the Interna- tional Collaborative Study, Elsevier/North-Holland, Amsterdam.

Ehrenberg, L., and S. Osterman-Golkar (1980) Alkylation of macromolecules for detecting mutagenic agents, Terat. Carcinogen. Mutagen., 1, 105-127.

Fleig, I., N. Petri and W.G. Stocker (1982) Cytogenetic analysis of blood lymphocytes of workers exposed to formaldehyde manufacturing and processing, J. Occup. Med., 24, 1009-1018.

Gebhart, E. (1982) The epidemiological approach: Chro- mosome aberrations in persons exposed to chemical muta- gens, in: T.C. Hsu, Allanheld and Osmun (Eds.), Cyto- genetic Assays of Environmental Mutagens, Ch. 18, pp. 385-408.

Gu, Z.W., B. Sele, D. Chmara, P. Salport, M. Vincent, P. Vincent, C. Marka and J. Faure (1981) Effects of trichloro- ethylene and its metabolites on the rate of sister chromatid exchange, In vivo and in vitro study on human lympho- cytes, Sem. Hrp., 57, 1511-1512 (Chem. Abstr., 96 (1982) 63980).

Harnden, D.G. (1976) Chromosome abnormalities and pre-dis- position towards cancer, Proc. Soc. Med., 69, 41-43.

Hirschorn, K., and M.M. Cohen (1968) Drug-induced chro- mosomal aberrations, Ann. N.Y. Acad. Sci., 151, 955-987.

Hogstedt, B., B. Gullberg, E. Mark-Vendel, F. Mitelman and S. Skerfving (1981) Micronuclei and chromosome aberrations

133

in bone marrow cells and lymphocytes of humans exposed mainly to petroleum vapours, Hereditas, 94, 179-187.

Hook, E.B. (1982) ICPEMC Working Paper 5/2; Perspectives in Mutation Epidemiology, Mutation Res., 99, 373-382.

ICPEMC (1980) Newsletter No. 3, Committee 1, B.J. Kilbey (Chairman), Mutation Res., 76, 217.

Kucerovh, M. (1982) Chromosomal aberrations induced in occupationally exposed persons, in: J.A. Heddle (Ed.), Mutagenicity - - New Horizons in Genetic Toxicology, Academic Press, New York, Ch. 9, pp. 241-266.

Miretskaya, L.M., and P.Y. Shvartsman (1982) Study of chro- mosomal damage to human lymphocytes due to formalde- hyde, Tsitologiya, 24, 1056-1060.

Preston, R.J., W. Au, M.A. Bender, J.G. Brewen, A.V. Carrano, J.A. Heddle, A.F. McFee, S. Wolff and J.S. Wassom (1981) Mammalian in vivo and in vitro cytogenetic assays, Muta- tion Res., 87, 143-188.

Purchase, I.F.H. (1978) Chromosomal analysis of exposed populations: A review of industrial problems, in: H.J. Evans and D.C. Lloyd (Eds.), Mutagen-lnduced Chromosome Damage in Man, Edinburgh University Press, Edinburgh.

Richardson, C.R., C.A. Howard, T. Sheldon, J. Wildgoose and M.G. Thomas (1984) The human lymphocyte in vitro cyto- genetic assay: positive and negative control observations on 30000 cells, Mutation Res., 141, 59-64.

Savage, J.R.K. (1976) Classification and relationships of in- duced chromosomal structural changes, J. Med. Genet., 13, 103-122.

Scott, D., N. Danford, B. Dean, D. Kirkland and C. Richard- son (1983) In vitro chromosome aberration assays, in: B. Dean (Ed.), Report of the UKEMS Sub-Committee on Guidelines for Mutagenicity Testing, UKEMS, Swansea.

Sobels, F.H. (1982) The parallelogram: An indirect approach for the assessment of genetic risks from chemical mutagens, Progr. Mutation Res., 3, 323-327.

Soper, K.A., P.D. Stolley, S.M. Galloway, J.G. Smith, W.W. Nichols and S.R. Wolman (1984) Sister chromatid exchange (SCE) report on control subjects in a study of occupation- ally exposed workers, Mutation Res., 129, 77-88.

Stolley, P.D., K.A. Soper, S.M. Galloway, W.W. Nichols, S.A. Norman and S.A. Wolman (1984) Sister chromatid ex- changes in association with occupational exposure to ethyl- ene oxide, Mutation Res., 129, 89-102.

Wolff, S. (1981) The sister chromatid exchange test, in: H.F. Stich and R.H.C. San (Eds.), Short-Term Tests for Chem- ical Carcinogens, Springer, New York, pp. 236-242.