Cock, J., de

Heederik, D.

Tielemans, E.

Wageningen Yield 

Occupational and Environmental Medicine 1995;52:429-430
Offspring sex ratio as an indicator of
reproductive hazards associated with
pesticides
Editor-De Cock et al` note that waiting
times to conception are significantly longer
in the wives of men exposed to pesticides.
They cite the evidence that the nematocide
dibromochloropropane (DBCP) is associat-
ed with diminished sperm counts.2 It is
worth noting that there is other evidence of
hazard in these men. They reportedly have
significantly high gonadotrophin concentra-
tions although their testosterone concentra-
tions remain normal.' I have hypothesised
that the sexes of human offspring are associ-
ated with the hormone concentrations of
their parents at the time of conception, high
testosterone producing boys, and high
gonadotrophin, girls.s7 In conformity with
this hypothesis, there is a highly significant
excess of daughters among the offspring of
male DBCP applicators."
So it would be interesting to know
whether there was an excess of daughters
among the 91 children sired by the pesticide
workers studied by de Cock et al.I More
generally, workers in industrial medicine
might consider offspring sex ratios as a cri-
terion of reproductive hazard: they are
cheaply and painlessly ascertained, and are
not subject to the measurement errors and
biases that characterise assessments of
sperm quality and hormone concentrations.
It should be noted that although a bias
towards daughters may be indicative of haz-
ard in male workers, there are no grounds
for supposing this in female workers. At any
rate, in any such analysis, the sex of off-
spring should be categorised by sex of
parent.
W H JAMES
The Galton Laboratory,
Department of Genetics and Biometry,
University College London,
Wolfson House, 4 Stephenson Way,
London NW1 2HE
1 de Cock J, Westveer K, Heederik D, Velde E
te, Kooij R van. Time to pregnancy and
occupational exposure to pesticides in fruit
growers in the Netherlands. Occup Environ
Med 1994;51:693-9.
2 Whorton D, Krauss RM, Marshall S, Milby
TH. Infertility in male pesticide workers.
Lancet 1977;ii: 1259-61.
3 Whorton D, Milby TH, Krauss RM, Stubbs
HA. Testicular function in DBCP exposed
pesticide workers. Occup Med 1979;21:
161-6.
4 James WH. The human sex ratio. Part 2: a
hypothesis and a program of research. Hum
Biol 1987;59:873-900.
5 James WH. Parental hormone levels and
mammalian sex ratios at birth. Theor Biol
1989;139:59-67.
6 James WH. The hypothesized hormonal con-
trol of human sex ratio at birth-an update.
Theor Biol 1990;143:555-64.
7 James WH. The hypothesized hormonal con-
trol of sex ratio at birth-a second update.
TheorBiol 1992;155:121-8.
8 Potashnik G, Yanai-Inbar I. Dibromo-
chloropropane (DBCP): an 8-year re-evalu-
ation of testicular function and reproductive
performance. Fertil Steril 1987;47:317-23.
Author's reply:
Editor-We would like to thank James for
his letter on offspring sex ratio among chil-
dren of fruit growers in our study on time to
a highly significant and large excess of
daughters among the offspring of male 1,2-
dibromo-3 chloropropane (DBCP) applica-
tors2 and wonders if information on sex
ratio is also available for the fruit growers in
our study. In our initial survey, we did not
gather these data. As data on sex ratio are
easy to obtain, we gathered this information
recently by telephone. We asked wives of
fruit growers the outcomes of their pregnan-
cies. Except for one pregnancy, we were
able to gather all the information on 140
pregnancies. The total number of pregnan-
cies was 127 (excluding 12 miscarriages for
which the sex ratio was unknown and one
pregnancy before the period of study). The
overall sex ratio was 0-51 with a 95% confi-
dence interval (95% CI) of 0-43-0 59
(based on a binomial distribution with
expected population value for sex ratio
(proportion of males) was 0-5143). For the
91 pregnancies in our time to pregnancy
study, the overall sex ratio was also 0-5 1.
In a more detailed analysis we first related
the sex ratio to the exposure variables that
were also studied in the time to pregnancy
study. A decrease in sex ratio was found
when recent years of birth were compared
with earlier pregnancies. Also, time to preg-
nancy increased with more recent years of
birth (table 1).
The most recent period (1987-90)
showed a lower sex ratio of borderline sig-
nificance (0-33) compared with the previous
periods (0 56) (Fisher's exact test, two
sided, P = 0-08). A similar trend in sex ratio
Table 1 Offspring sex ratio and time to
pregnancy according to year of birth (n = 85) *
Time to
Year of Pregnancies pregnancy
birth n Sex ratio (months)
1978-80 18 0-56 2-9
1981-83 22 0-55 3-5
1984-86 24 0-58 4-2
1987-90 21 0-33 4-1
*n = 91 pregnancies from the time to pregnancy
study, excluding six miscarriages of unknown sex.
1-0
CL
m 0-8
0-7
° 0-6
CL
O 0.5
0
C
C 0.4
E 0.3
0
a 0.2 -
.0-1 __
0 0.0 I
0 1 2 3 4 5 6 7
Time t
was found for the total group of 127 preg-
nancies. We also found a change in sex ratio
dependent on gravidity. For the first, sec-
ond, third, and subsequent children, sex
ratios of 0-60, 0 57, 0-42, and 0-31 were
found respectively. The first two pregnan-
cies of a couple in comparison with next
pregnancies showed a sex ratio of 0-58 and
0-38 respectively (Fisher's exact test, two
sided, P = 0 08).
This raises the question whether gravidity
acts as a confounder in this analysis, as does
time to pregnancy. Because of small num-
bers, stratification of sex ratio according to
gravidity and year of birth was not possible.
Surprisingly, a difference in time to preg-
nancy according to year of birth was found
for boys but not for girls. The figure is a
Kaplan-Meier curve (PROC LIFETEST)
by year of birth for boys. The curves, did
not differ significantly. A univariate survival
analysis with the PHREG SAS procedure as
described in our study on time to preg-
nancy,' for the period of birth comparing
pregnancies occurring in 1983 or before (1)
with more recent pregnancies (0) as the
independent variable, showed a fecundabili-
ty ratio of 1-61 (95% CI 0-83-3-13) for
boys and 1-13 (95% CI 0-59-2-15) for girls.
No differences in age at the time of concep-
tion of men or women, or the age difference
between both parents were found in our
study. Therefore, a role of age dependent
hormone concentrations of the parents on
offspring sex ratio at the time of conception
is not a very likely explanation for these
findings.
In our study on time to pregnancy, we
focused on seasonal effects of exposure of
men. No significant differences according to
season were detected in the sex ratios.
Observed sex ratios for the quarter of a year
in which conception took place were: 0-64
(January-March), 0 44 (April-June), 0-48
(July-September), and 0-52 (October-
December).
As no relation between sex ratio and any
of the exposure variables used in our study
on time to pregnancy was found, other
available information on exposure was con-
sidered as well. Because offspring sex ratio
is a dichotomous variable, we studied out-
come in a case-control like design with
maximum likelihood logistic regression
models by computing odds ratios (ORs)
with SAS PROC LOGISTIC. As the odds
o Pregnancies <1983
o Pregnancies >1984
7 8 9 10 11 12 13 14 15 16 17 18
to pregnancy (months)
Time to pregnancy by year of birth for boys (n = 44).
CORRESPONDENCE
429
pregnancy. I In his letter James refers to
 group.bmj.com on December 23, 2011 - Published by oem.bmj.comDownloaded from 
Letters
Table 2 Odds ratios of 16 cases (more
daughters than sons within a family) compared
with 27 controls (43 sons) for exposure variables
Odds ratio
Variable (95% CI)
Spraying days 1990 18-4 (1-72-196)
(30 days)
Cross current sprayer 1-7 (1-05-2-59)
(10 days/y)
Herbicide sprayer (5 days/y) 3-6 (1-10-11-6)
(Manual) knapsack sprayer 2-2 (1064-66)
(5 days/y)
Metiram (1 spraying/y) 1-3 (1-05-1-61)
Azinphos-methyl (0/1) 4-4 (1-11-17-3)
Paraquat (0/1) >5-6* (>5 6-< 13-4)
*Paraquat was used by all families with more
daughters compared with 74% in the control
group.
ratio for gravidity (OR 1-35, 95% CI
0 92-1 99) was not significant and adjust-
ment did not influence the regression coeffi-
cient or standard errors of variables of
interest, only crude ORs are given.
No relation was found for most of the
variables studied in our time to pregnancy
study, but the results suggest a relation
between use of a cross current airblast
sprayer (days/y) (OR= 1-3, 95% CI
0-96-1-72) and use of a herbicide sprayer
(days/y) (OR= 2-0, 95% CI 1-08-3-76)
and production of daughters. Also we com-
pared families with more daughters than
sons with the other families. Instead of
gravidity we corrected for the number of
children within a family (OR = 1-23, 95%
CI 0-66-2-31). As some families also con-
ceived children before the time of the study
(1978-90) number of children is a surro-
gate measure for gravidity. Because differ-
ences with or without adjustment were
small, table 2 gives only crude ORs. For the
43 families a relation was found between
the number of days with use of a herbicide
sprayer (days/y), a cross current airblast
sprayer (days/y), and a knapsack sprayer
(days/y) and the number of daughters within
a family. When comparing families with
more daughters than sons (16 families), the
number of spraying days a year was 37
compared with 25 for the other families, 7-6
v 3-3 days/y for the herbicide sprayer, 16 v
5-4 days/y for the cross current airblast
sprayer, and 7-1 v 3 0 days/y for the knap-
sack sprayer. In families with more daugh-
ters use of the specific pesticides Azinphos-
metyl (insecticide), Metiram (fungicide),
and Paraquat (herbicide) was higher. Table
2 shows the results of the ORs.
For families with more sons than daugh-
ters (17) a significant OR was found for use
of a cross current sprayer (yes or no, OR =
0-16, 95% CI 0 03-0-82), and number of
spraying days with this type of sprayer (OR
= 0-54 per 10 spraying days/y, 95% CI
0-30-0 98).
Discussion
Overall sex ratio was not different from the
expected ratio of 0-51. James hypothesised
that high concentrations of testosterone at
the time of conception produce boys, and
high concentrations of gonadotrophin pro-
duce girls. Among the offspring of DBCP
applicators3 a highly significant excess of
daughters was found. As exposure to pesti-
cides in fruit growing typically includes
mixed exposure to many different com-
pounds, similar to that found for DBCP, it
is not possible to predict the direction of a
shift in sex ratio induced by exposure to
pesticides among this group. As the number
of subgroups is small it is impossible to
draw firm conclusions, but some of the
results are of interest. From our results
there are some indications that exposure to
pesticides in agriculture may affect offspring
sex ratio. The shift towards daughters in the
most recent period (sex ratio of 0 33) was
remarkable. Also the finding that spraying
frequency, frequency of use of specific
equipment, and use of some specific pesti-
cides are related to a shift towards more
daughters within a family may point to an
exposure effect. One should be careful in
interpreting these results. The fact that use
of several pesticides is related to sex ratio
does not necessarily imply that individual
pesticides are causally related to sex ratio.
Fruit growers use a complex mixture of
agents and the use of one agent is often cor-
related with the use of another one. It is
unlikely that the shift in sex ratio is caused
by the introduction of particular pesticides
as all pesticides have been applied to some
extent during the study period. Because
application techniques changed consider-
ably over time, the introduction of certain
techniques seems a more plausible explana-
tion for this finding. It is possible that with
certain underlying mechanisms, effects may
not be caused by exposure of the male
worker only, as most women live near the
orchard and they often participate during
particular activities like pruning, thinning,
and harvesting. No seasonal trends were
found in this analysis as was found for time
to pregnancy. Our finding that there might
be a difference in time to pregnancy for
boys and girls as well, may indicate that
both sex ratio and time to pregnancy are
interlinked. We cannot explain why expo-
sure variables associated with time to preg-
nancy are not related to sex ratio.
In conclusion, we think that the sugges-
tion by James to analyse sex ratio is a useful
one and should be explored further. To
consider both sex ratio and time to preg-
nancy simultaneously may have advantages
in elucidating occupational hazards of (pes-
ticide) exposure. Our results do show that
other variables such as families with pre-
dominantly daughters or sons, which are
indicative of a shift in sex ratio, might be
more powerful because they use another
sampling unit (family instead of a crude
stratification by exposure). Especially in this
study among agricultural workers an analy-
sis on a family level might be relevant
because the exposure might be aggregated
at the family level as well. In general, it
seems useful to explore, after time to preg-
nancy and sex ratio, the presence of families
with a predominance of one of the sexes as
little is known about the underlying biologi-
cal mechanisms as well as the statistical
properties of these indices.
JOHAN DE COCK
DICK HEEDERIK
ERIK TIELEMANS
Department ofEpidemiology and Public Health,
Wageningen Agriculural University, PO Box 238,
6700 EA Wageningen, The Netherlands
EGBERT TE VELDE
ROEL VAN KOOIJ
Department of Obstetrics and Gynaecology,
section Fertility,
Academic University Hospital Utrecht,
The Netherlands
1 Cock J de, Westveer K, Heederik D, Velde E
te, Kooij R van. Time to pregnancy and
occupational exposure to pesticides in fruit
growers in The Netherlands. Occup Environ
Med 1994;51:693-9.
2 Ptashnik G, Yanai-Inbar I. Dibromo-
chloropropane (DBCP): an 8-year re-evalu-
ation of testicular fiction and reproductive
performance. Feril Steril 1987;47:317-23.
3 James WH. Sex ratio of offspring as a criterion
of occupational hazard, with reference to
welding. Scand J Work Environ Health
1994;20:466-7.
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doi: 10.1136/oem.52.6.429-a
 1995 52: 429-430Occup Environ Med
 
W H James
 
pesticides.
reproductive hazards associated with 
Offspring sex ratio as an indicator of
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Offspring sex ratio as an indicator of reproductive hazards associated with pesticides.

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