et al. report a strong association between testicular
cancer risk for a man and the levels of organochlorines in his mother's
serum. They found only a limited link between OCs in the
man's own blood and the likelihood of developing testicular cancer.
testicular cancer is a disease primarily of young adulthood (see
figure, below), growing evidence points to developmental
failure in the fetal testis as its principal origin. A number
of factors have been suggested as possible causes of this developmental
failure, including endocrine disrupting chemicals.
Evidence supporting the role of EDCs, however, has been circumstantial
and indirect: Dramatic
increases in the incidence of testicular cancer over time
suggest an environmental link. Associations between testicular
cancer and 3 other testicular maladies (impaired sperm quality,
cryptorchidism and hypospadias) suggest a common origin and
have been linked in what is now called the "testicular
dysgenesis syndrome." EDC compounds can induce these
other maladies in laboratory animals.
graph above shows the incidence rate of the two principal
forms of testicular cancer as a function of age at diagnosis.
Most cases are diagnosed in men between the ages of 20-35
years of age. While these data are from the Netherlands
1989-1996, they are typical for the pattern of testicular
cancers around the world.
animal model for testicular cancer is currently known, however,
and only limited epidemiological
evidence links hormonal exposures in the womb to testicular
cancer in humans.
new study by Hardell et al. presents the strongest epidemiological
link reported to date between testicular cancer and endocrine-disrupting
did they do? Hardell et al. recruited men newly
diagnosed with testicular cancer in several Swedish hospitals, along
with their mothers, to participate in the study. Each man with testicular
cancer was matched with a control (without testicular cancer) drawn
from the Swedish population registry. To eliminate confounding variables
associated with age, each patient/mother pair was matched with a
control/mother pair in which the control and the control's mother
were close in age (within 5 years) to the patient and mother to
whom they were matched, respectively.
was obtained from each participant in the study and then analyzed
for a series of organochlorine contaminants: 38 PCB congeners (summed),
hexachlorobenzene (HCB), p,p'-DDE, and six chlordane congeners.
et al. then calculated odds ratios for the risk of testicular
cancer in relation to contamination levels, in both mothers and
did they find? Hardell et al. analyzed the blood
of 58 case-control pairs, 44 mothers of cases, and 45 mothers of
found little difference between the contamination levels of the
men with testicular cancer and their age-matched controls. Only
one contaminant, a congener of chlordane (cis-nonachlordane) showed
an elevated risk, with an odds ratio of 2.6. The 95% confidence
interval for this odds ratio ranged from 1.2 to 5.7.
of the mothers yielded markedly different results. Highly
significant differences (all p < 0.01) were observed
comparing the concentrations of three of the organochlorine measurements
in case mothers vs. control mothers: PCBs
(summed, p = 0.0006); HCB (p = 0.005) and Cis-nonachlordane
(p = .008). All chlordane congeners summed was marginally significant
(p = .04).
odds ratios for four of the organochlorine measurements (bold in
table below) were elevated substantially, with the lower limit of
their 95% confidence intervals each exceeding 1.
adapted from Hardell et al. In addition to displaying the
odds ratio and 95% confidence intervals, this table shows the number
of cases and controls which exceeded the median concentration level
for each organochlorine measurement. For example, while only 20
of the controls exceeded the median value for summed PCBs, 34 of
the men with testicular cancer did.
does it mean? Hardell et al.'s central findings
are that (1) mothers with higher organochlorine
levels are significantly more likely to have given birth to sons
who develop testicular cancer; and (2) in contrast, the
sons themselves for the most part do not have elevated organochlorine
levels compared to men without testicular cancer.
this result falls short of proving that developmental disruption
by organochlorine contamination in the womb sets the stage for testicular
cancer in adulthood, it strengthens the case significantly. No other
mechanism would be consistent with the the central findings of this
are the study's weaknesses?
sample size is relatively small. Nonetheless the results are highly
study assumes that measurement of OCs in a mother's serum on average
some 30 years after the son's birth provides useful information
about exposure levels experienced in the womb. The studied organochlorines
are highly persistent, lending some legitimacy to this assumption.
If were not true, moreover, it is highly unlikely that results
of the significance level reported here would be found.
study has no information about exposure to non-persistent endocrine
disrupting compounds, for example phthalates, established by animal
experiments to disrupt development of the fetal testis. Many if
not all of the sons in this study were surely exposed transiently
in the womb to some--possibly many--of these contaminants. But
the presence of these other agents, if they too interfere with
fetal testis development, would be more likely to increase the
likelihood of false negatives rather than false positives. Hence
the fact that the results are strongly significant even without
controlling for other agents indicates that these results are
real, not artifactual.
research also provides an important reminder that exposure
measurements at the time of diagnosis of adult diseases are inappropriate
for epidemiological studies in which risks are established during
windows of vulnearbility early in life. Almost all the
comparisons of organochlorine contamination of cases and controls
in this study were nonsignificant. The one (cis-nonachlordane) that
was positive has a modest elevation in risk (odds ratio = 2.6) but
the confidence limits were broad.