International Journal of Epidemiology Vol. 24, No.

5
O International Epldemlotoglcal Association 1995 Printed in Great Britain

A Case-Control Study of Aplastic

Anaemia: Occupational Exposures
M GUIGUET,* E BAUMELOU,* J Y MARY* AND THE FRENCH COOPERATIVE GROUP FOR
EPIDEMIOLOGICAL STUDY OF APLASTIC ANAEMIA

Gulguet M (INSERM U263, Centre de Blolnformatique, Universite Paris 7, 2 place Jussieu, 75005 Paris, France),

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Baumelou E, Mary J Y and the French Cooperative Group for the Epidemiological Study of Aplastic Anaemia. A case-
control study of aplastic anaemia: Occupational exposures. International Journal of Epidemiology 1995; 24: 993-999.
Background. Based on the national register of new cases of aplastic anaemia (AA) begun in France in 1984, a case-
control study was conducted to explore the aetiology of the disease.
Methods. Cases were all included in the French national register of AA. Two different groups of controls were derived
with individual matching; one group from hospitalized patients In the same hospital; the other group from neighbours
named by the case. A 15-year occupational history was collected through interview and then grouped into exposure
categories by jobs done for one year or more. The study Included 98 cases, 181 hospitalized controls, and 72 neighbours
aged 18-70 years.
Results. No differences appeared between the cases and both groups of controls relative to any group of occupation
investigated. However, a borderline non-significant small excess for exposure to pesticides was observed among the
cases when compared to hospitalized controls. Whatever the control group, no association was found between AA and
exposure to solvents, ionizing radiation, fuel, oils and grease. A positive relationship between exposure to glues and AA
was observed, as well as a trend towards an increased risk after exposure to paints.
Conclusions. This large-scale case-control study confirmed the vanishing role of previously known toxic substances In
the aetiology of AA. However, a higher proportion of AA patients reported exposure to paints and to glues, a relationship
which needs further investigation because of the diversity of compounds included in these products.
Keywords: aplastic anaemia, occupational risk, job history, case-control study

Aplastic anaemia (AA) is a rare but severe haem-
atological disease, often of unknown origin. In a recent
French study by Mary et al.' the annual incidence rate
was 1.5 per million inhabitants, the fatality rate was
34% one year after diagnosis and 74% of new cases
were declared idiopathic by physicians in charge of the
patients. Medical history, therapeutic drugs and envir-
onmental factors have all been implicated.2'3 Some
effects concerning the relationship between occupa-
tional exposure and the occurrence of AA have been
well documented, e.g. benzene4"3 or radiation expos-
ure,6 but these are now disappearing as a result of either
replacement of the toxic substance,7-8 increased protec-
tion and control of the exposure level.9 Conversely,
some toxic effects are still being debated due to the lack
of consistency of published results. The relationship
between AA and pesticides remains controversial, with
many case reports suggesting their possible role.10"13
• INSERM U263, Centre de Bioinformalique, University Pari» 7,
2 place Jiusieu, 75005 Paris, France.
Reprint requests to: M Guiguet, INSERM U263, CHU St-Antoine,
27 me Chaligny, 75012 Paris, France.
993
However, no toxic effect has been shown in epi-
demiological studies. 1415
The high number of cases of unknown origin, the
diminishing effects of known toxic substances due to
modification of exposure levels or increase in protec-
tion as well as debatable aetiologies justify the reassess-
ment of the risk of AA associated with occupational
exposures. Such studies were performed simultaneously
in the US 16 and in France. Our case-control study,
based on the national register of aplastic AA initiated in
1984,' was conducted in 1985-1988. This study has
been previously analysed for drug associated risks.17
The results presented here are that part of our study
assessing toxic exposures.
MATERIAL AND METHODS
Selection of cases and controls has already been des-
cribed in detail.17 A diagnosis of AA required at least
two depressed blood cell lineages: haemoglobin
< 1 0 g / 1 0 0 m l and reticulocytes < 5 0 x l 0 9 / l , poly-
morphonuclears <1.5xlO 9 /l, platelets < 1 0 0 x l 0 9 / l ,
and a bone marrow biopsy specimen with decreased
994 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
cellularity compatible with the disease and showing no
significant fibrosis or neoplastic infiltration. Patients
coming from abroad for treatment and those with con-
stitutional disease (e.g. Fanconi anaemia) were ex-
cluded. Moreover, the study was restricted to cases
aged 18-70. During the study period, 222 cases of an
appropriate age were recorded in the register and, of
these, 98 were included in the case-control study con-
cerned with occupational history. The other cases were
not interviewed as either no investigator was available
at that time in the centre or the investigator, already
involved in another case, did not have time to conduct
the interviews. However, using information recorded in
the national register, we verified that there was no dif-
ference in sex, age, place of residence, or severity of
the disease (classified using Camitta et al.'s criteria) 18
between cases included in the case-control study and
those who were not.
For each case included in the case-control study,
three controls, matched on sex and age (± 5 years),
were required. After exclusion of patients with malig-
nant diseases or those hospitalized in an intensive care
unit, the first two controls were selected systematically
from the hospital admission registry among those pa-
tients hospitalized in the same hospital as the case. The
third control had to be named by the case from among
his/her neighbours. Ninety-eight cases were included,
as well as 181 hospitalized controls (87 sets with two
hospitalized controls and seven sets with one hospital-
ized control) and 72 neighbours. Only one hospitalized
control did not respond about his/her professional his-
tory. Where neighbour controls are missing, it is
because the case refused to provide any neighbour's
name. Missing hospitalized controls correspond either
to the absence of an adequate control in the period or to
interruption of the work of the investigator.
Information about medical history, drug intake and
occupation was collected by trained interviewers; the
same interviewer interviewed the case and its controls.
During the interview, the subject's professional history
over the last 15 years was investigated. For each long-
term occupation, done for one year or more, data des-
cribing the tasks, exposures, environmental conditions
and protection were collected. This information was
examined by a single toxicologist, blinded to the case/
control status of the subject, to determine if an exposure
should be attributed or not to each component using a
predefined checklist. The exposure was graded by the
toxicologist at two levels (low or 'large') according to
both intensity and frequency.
Occupations were coded following the International
Standard Classification of Occupations (BIT). For each
occupation, a binary variable was defined according to
whether or not the occupation had been done for at least
one year. Each subject could have been assigned to
more than one job. The toxic exposures were invest-
igated across all jobs and coded by the highest exposure
level recorded. The first analysis compared the exposed
subjects, whatever their level of exposure, to the non-
exposed subjects. Subsequent analysis was restricted
to subjects exposed at a Marge' level versus those who
were not exposed.
Statistical analysis was conducted according to the
matching design with a variable number of controls."
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Each group of controls—hospitalized or neighbours—
was considered separately. When no difference in ex-
posure was observed between the hospitalized controls
and the neighbours, and if the same trend was obtained
in the comparisons between cases and each category of
controls, a global analysis was performed by combining
both types of controls. When dealing with several fac-
tors together, logistic regression was employed using a
conditional regression model.19
Assuming that the proportion exposed among the
controls would be 0.1, an odds ratio (OR) greater than
3.5 could be detected in the case-neighbour comparison
(72 sets with matching ratio = 1:1; type I error = 5%;
power = 80%), and an OR greater than 2.6 could be
detected in the case-hospitalized control comparison
(84 sets with matching ratio 1:2, and seven with match-
ing ratio 1:1; type I error = 5%; power = 80%). For a pro-
portion of exposed controls expected at 0.3, OR likely
to be detected were 2.5, and 2.3, for case-neighbour and
case-hospitalized controls comparisons, respectively.20
RESULTS
Table 1 shows the matched OR of AA for major groups
of occupations and some specific occupations. None
were found to be associated with an increase in AA
when the cases were compared to the hospitalized con-
trols, or to their neighbours. In particular, no excess risk
was observed for the group 'agricultural, animal hus-
bandry, and forestry workers, fishermen and hunters'
which, in our sample, included only fanners. A history
of construction work was associated with AA but only
when comparing cases to the hospitalized controls, and
the small sample size for this occupation limited the
accuracy of the estimate of risk.
The list of toxic substances which were evaluated is
presented in Table 2, with the proportion of exposed
controls. The exposure was similar in both groups
of controls, except for pesticides, for which neighbours
were more exposed, whatever the level of exposure.
Comparisons between AA patients and controls are pre-
sented in Table 3. There was absolutely no difference
 OCCUPATIONAL EXPOSURES AND APLASTIC ANAEMIA 995

TABLE 1 Occupations and aplastic anaemia (International Standard Classification of Occupations)

Cases versus hospitalized Cases versus neighbours

C 1
N+/N-' OR" 9 5 * CI N+/N- ORb 95% CI*

Major groups of occupations

Professional, technical, and related workers (011-199) 8/21 0.7 (0.3-1.5) 3/10 0.3 (0.08-1.1)
Administrative and managerial workers (201-219) 3/1 2.7 (0.3-27.3) 0/1 NEd
Clerical and related workers (300-399) 9/22 0.7 (0.3-1.5) 6/5 1.2 (0.3-9.2)
Sales workers (400-490) 10/12 1.4 (0.6-3.3) 4/0 NE (0.7--)
Service workers (500-599) 10/30 0.4 (0.2-0.9) 7/9 0.8 (0.3-2.1)

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Agricultural, animal husbandry, and forestry workers.
fishermen, and hunters (600-649) 8/9 1.6 (0.6-4.1) 1/8 0.1 (0.02-1.0)
Production and related workers, transport equipment
operators, and labourers (700-999) 27/19 1.6 (0.8-2.9) 13/7 1.9 (0 7-4.7)

Specific occupations
Automechanics and service station employees
(843, 451^»9O) 1/5 0.4 (0.06-3.4) 1/1 1.0 (0.06-16.0)
Construction workers (950-959) 8/3 4.8 (1.2-18.7) 3/1 3.0 (0.3-28.8)
Painters (930-939) 1/4 0.5 (0 06-4.5) 0/0 NE

• N+ and N- are the number of discordant matched sets in which either the aplastic anaemia (AA) patient was exposed and at least one control was
not, or the AA patient was unexposed and at least one control was.
b
Odds ratio.
C
95% confidence interval.
d
Not evaluable.

between the cases and the neighbour controls for
history of occupational exposure to pesticides, but a
borderline non-significant difference appeared when
comparing cases to hospitalized controls. There was no
evidence of an increased risk for those exposed to any
of the investigated categories of solvent.
Cases were at least twice as likely as both groups of
controls to have been exposed to glues, a relationship
still present after restriction to the 'large' level of ex-
posure. When both groups of controls were combined,
the association was always significant with a global OR
equal to 2.7 (95% C I : 1.5-5.0) and 2.8 (95% C I : 1.3-
6.2) for all and 'large' exposure, respectively. The same
trend towards an increased risk after exposure to paints
was observed with both categories of controls, with OR
of 1.8 (95% C I : 1.0-3.4) and 1.8 (95% C I : 0.8-4.2)
for all and 'large' exposure, respectively. When using
the conditional regression model for any or 'large'
exposure to paints and glues, the association with AA
remained only for glues with an OR of 2.8 (95% C I :
1.3-5.8) and 3.2 (95% CI : 1.0-10.2) for any and
'large' exposure, respectively. Amongst those exposed,
the length of exposure to glues did not differentiate
between the case or control subjects, with an equal
median duration of 6 years. For paint exposure, the
median durations were also comparable between the
cases (10 years) and the controls (8 years).
None of the other exposures investigated was
associated with AA.
DISCUSSION
In a case-control study, selection of controls is crucial,
and in the present study, two groups of controls were
investigated. The first group was composed of patients
admitted to the same hospital as the cases. Among these
hospitalized controls no specific disease was over-
represented,17 and this diversity prevented any potential
bias due to hospitalization for specific diseases related
to some occupational exposures. However, a potential
referral bias could not be excluded as the hospitals have
specific specialities for different pathologies, implying
that cases and hospitalized controls may not reflect a
population from the same area. This was confirmed
when looking at the number of inhabitants by their
place of residence. The AA patients were more likely
to live in rural places (<2000 inhabitants) than the
hospitalized controls (33% versus 17%), while no dif-
ference was observed with the neighbours (37%).
The second group of controls, taken from the general
population, were personally named by the cases
from among his/her neighbours. This geographical
overmatching could never be totally excluded, espe-
cially for occupational exposures. Clearly, neither of
996 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY

TABLE 2 Toxic substances evaluated and exposure" among the control subjects

Hospitalized controls Neighbours

N= 181 N = 72

n (%)

Pesticides
all types 24 (13) 17 (24)
insecticides 24 (13) 17 (24)
11 (6) 10 (14)
weedkillers 18 (10) 14 (19)
10

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10 (6) (14)
fungicides 20 (11) 15 (21)
11 (6) 9 (12)
Solvents
all types 94 (52) 40 (55)
hydrocarbon solvents 89 (49) 40 (55)
59 (32) 28 (39)
halogenated solvents 81 (45) 37 (51)
46 (25) 16 (22)
oxygenated solvents 81 (45) 34 (47)
53 (29) 19 (26)
Glues 28 (15) 15 (21)
15 (8) 4 (6)
Paints 31 (17) 18 (25)
18 (10) 5 (7)
Fuel 9 (5) 6 (8)
2 (1) 2 (3)
Oils and grease 48 (26) 27 (37)
31 (17) 10 (14)
Ionizing radiation 7 (4) 3 (4)
2 (1) 0 (0)
Magnetic fields 4 (2) 5 (7)
2 (1) 1 (1)

* Exposure was defined as (+) any exposure during the investigated period, or (++) a large level of exposure.

these two control groups were perfect. Nevertheless,
careful analysis of differences in exposure levels be-
tween the two groups of controls and in the association
with AA according to control group, emphasizes the
importance of having these two groups. The ideal con-
trol group lies somewhere in between, according to
each factor studied.
In this study we considered occupational exposures
which occurred during jobs done for at least one year.
Many respondents reported short-term occupations,
13% for the cases, 15% and 13% for the hospitalized
and neighbour controls, respectively. In addition, occu-
pational exposures resulting from unofficial jobs were
probably not reported to the interviewers. If these jobs
resulted in intense, although short-term exposures, a
more detailed interview would have been required to
detect them.
Occupational exposures were assessed by a two-
stage process. Work history was obtained from each
subject during an interview, and exposures were co-
ded at a second stage by a toxicologist. This approach
has often been used when no job-exposure matrix
was available. Classification of exposure into the 'low'
or 'large' category was performed by a single toxic-
ologist using information on the job, the description
of the tasks done, and environmental conditions and
protection reported during the interview. Because of
the relatively high proportion of controls with low
exposure, it is likely that the category, 'low' exposure,
was rather wide. In any case, as the classification was
performed blindly by the same toxicologist, no bias
could be introduced in the comparison between cases
and controls.
No relationship was found between any major group
of occupations and AA. This supports the lack of sys-
tematic selection bias. Only one major occupational
group, farming, was studied for its hypothetical rela-
tionship with AA. In accordance with the difference
 OCCUPATIONAL EXPOSURES AND APLASTIC ANAEMIA 997

TABLE 3 Occupational exposures' and aplastic anaemia

Cases versus hospitalized Cases versus neighbours

N+/N- b ORC 95% O6 N+/N- b ORC 95% CI*

Pesticides
all types 18/18 1.6 (0.8-3.0) 4/10 0.4 (0.1-1.3)
insecticides 18/18 1.6 (0.8-3.0) 4/10 0.4 (0.1-1.3)
11/8 2.3 (0.9-5.8) 1/5 0.2 (0.02-1.7)
weedkillers 15/15 1.7 (0.8-3.6) 4/9 0.4 (0.1-1.4)
9/8 2.0 (0.8-5.3) 2/6 0.3 (0.1-1.6)

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fungicides 17/15 1 8 (0.9-3.7) 5/9 0.6 (0.2-1.7)
12/8 2.5 (1.0-6.2) 4/5 0.8 (0.2-3.0)
Solvents
all types 27/28 0.9 (0.5-1.7) 10/16 0.6 (0.3-1.4)
hydrocarbon solvents 26/29 1.0 (0.6-1.7) 8/16 0.5 (0.2-1.2)
19/18 1.2 (0.6-2.3) 6/13 0.5 (0.2-1.2)
halogenated solvents 28/23 1.2 (0.7-2.1) 11/16 0.7 (0.3-1.5)
16/14 1.3 (0.6-2.7) 5/7 0.7 (0.2-2.3)
oxygenated solvents 23/30 0.8 (0.5-1.4) 11/17 0.6 (0.3-1.4)
13/17 0.8 (0.4-1.6) 6/9 0.7 (0.2-1.9)
Glues 28/16 2.7 (1.5-5.1) 13/5 2.6 (0.9-7.3)
16/9 2.7 (1.2-6.1) in 4.0 (0 8-18.8)
Paints 24/14 2.3 (1.1—4.5) 8/7 1.1 (0.3-3.7)
13/9 19 (0.8-4.5) 6/2 3.0 (0.6-14.9)
Fuel 3/8 0.6 (0.2-2.4) 2/5 0.4 (0.1-2.1)
in 1.7 (0.2-12.7) in 1.0 (0 1-7.1)
Oils and grease 25/23 1.3 (0.7-2.3) 7/14 0.5 (0.2-1.2)
14/16 1.0 (0.5-2.1) 3/4 0.7 (0.2-3.3)
Ionizing radiation 3/7 0.9 (0.2-3.3) 3/3 1.0 (0.2-5.0)
1/2 1.0 (0.1-11.0) 1/0 NP (0.02—)
Magnetic fields 1/3 0.3 (0.03-4.1) 0/3 NE
0/1 NE 0/1 NE

1
Exposure was defined as (+) any exposure during the investigated penod, or (++) a large level of exposure; the reference group being people who
were not exposed.
b
N+ and N - are the number of discordant matched sets in which either the aplastic anaemia (AA) patient was exposed and at least one control was not,
or the AA patient was unexposed and at least one control was.
c
Odds ratio.
d
95% confidence level.
'Not evaluable.

in residential location, the percentage of agricultural
workers was different between the two groups of
controls, with 6% and 17% among the hospitalized
controls and the neighbours, respectively. The national
percentage of agricultural workers was 8% in 1985.2I
Therefore, a comparison of agricultural occupational
exposure was undertaken between the AA cases and the
hospitalized controls and no excess of cases was
observed. A previous descriptive study of 251 French
AA cases suggested excess frequency in the rural
population. 22 However, subsequent epidemiological
studies did not support this association. A cohort
study has indicated an excess of AA mortality for
farmers, but the excess was not consistently observed
after I960. 13 A case-control study of fatal A A was
unable to find any increasing risk among people who
reported farming, landscaping, gardening or pest
exterminating.14 A positive association between AA
and exposures to pesticides has been postulated as a
result of case reports.10"13 When exposure to pesticides
was directly investigated, no risk was observed in the
comparison with neighbours but the diminishing
numbers of pairs could indicate a possible over-
matching between cases and neighbours. Exposure to
pesticides was associated with a moderate, borderline,
non-significant risk when cases were compared to the
hospitalized patients. Whatever the categories, the OR,
even if not reaching statistical significance, were
increased after restriction of the exposure to the Marge'
level. In the study presented here, only occupations
998 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
done after the 1970s were investigated, and, if there is
still a risk, it could currently be low.
In our study, no significant risk was detected for
agents with recognized bone marrow toxicity. No asso-
ciation was found between AA and occupational radia-
tion exposure. Another recent case-control study found
OR equal to 1.0 for occupational exposure to radia-
tion. 16 The mortality trends in successive cohorts of
radiologists indicated that the excess risk of AA dra-
matically decreased for those entering this speciality
after 1940.9 In the same way, the relationship which
was reported between airborne concentration and ben-
zene poisoning led to reduced exposure. In a retro-
spective cohort study of workmen exposed to benzene
conducted in the US, no excess of mortality from AA
was observed.7 In our study, no difference was noted
between cases and controls for exposure to solvents.
Coding of exposure resulted in a high frequency of
exposed subjects which is difficult to interpret in the
absence of external information. It was however coded
blindly and the resulting measure of association re-
mains valid. As the chemical exposures could have
been modified over the years due to replacement of
solvents, the crude evaluation of past exposure to dif-
ferent solvents could have failed to detect any asso-
ciation. In countries where replacement of the toxic
substance has taken place, or where there has been an
increase in protection and control of the exposure level,
case-control studies could be limited in their ability to
detect residual risk.
Our results suggest a positive relationship between
exposure to glues and AA. The risk estimates were con-
sistent whatever the group of controls used for the
comparison or the level of exposure investigated. An
elevated risk, though of borderline significance, was
found for exposures to paints when comparing the cases
to both categories of controls. The other case-control
study that explored the occupational exposure to paints
has shown an increased risk of AA. 16 In our study,
many cases and controls were exposed to both paints
and glues and it is difficult to differentiate the roles
played by each exposure even if the association with
AA was only evident for glues in a multivariate ana-
lysis. For each of these exposures, glues or paints, the
positive association with AA could not be explained
by confounding with risk factors previously demon-
strated;17 either medical history (rheumatoid arthritis)
or drug use (gold salts, indomethacin, colchicine or
allo/thiopurinol). Paints and glues are a mixture of
different compounds and both products associate resin
and solvent, even if considerable diversity exists among
these components. The independent indicative findings
of an association of AA with either paints or glues lends
suspicion to these mixtures which will need to be better
investigated in future studies.
In conclusion, this large-scale case-control study
confirmed the vanishing role of previously demon-
strated toxic substances related to the occurrence of
AA. Nevertheless, findings showed a borderline non-
significant association with pesticides and an associa-
tion with glues and/or paints was noted. The latter
clearly requires further study to investigate the various
individual compounds contained in these products.
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ACKNOWLEDGEMENTS
This work was supported by a grant from the Ministere
des Affaires Sociales et de la Solidarity Nationale,
Direction G6n6rale de la Sante\ and by Grants
No. 850017 and 489018 from INSERM. This study
would not have been possible without the co-operation
of the 83 medical centres that participated in the French
National Registry of Aplastic Anemia cases. We are
grateful to A Carrigou for his expertise, to all the
interviewers who participated in the study, and to
J Chwalow for revising the text.
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