2,3,7,8-Tetrachlorodibenzo-p-dioxin plasma levels in Seveso 20 years after the accident.
ABSTRACT In 1976, near Seveso, Italy, an industrial accident caused the release of large quantities of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) into the atmosphere, resulting in the highest levels of the toxicant ever recorded in humans. The contaminated area was divided into three zones (A, B, R) corresponding to decreasing TCDD levels in soil, and cohort including all residents was enumerated. The population of the surrounding noncontaminated area (non-ABR) was chosen as referent population. Two decades after the accident. plasma TCDD levels were measured in 62 subjects randomly sampled from the highest exposed zones (A and B) and 59 subjects from non-ABR, frequency matched for age, gender, and cigarette smoking status. Subjects living in the exposed areas have persistently elevated plasma TCDD levels (range = 1.2-89.9 ppt; geometric mean = 53.2 and 11.0 ppt for Zone A and Zone B, respectively). Levels significantly decrease by distance from the accident site (p = 0.0001), down to general population values (4.9 ppt) in non-ABR, thus validating the original zone classification based on environmental measurements. Women have higher TCDD levels than men in the entire study area (p = 0.0003 in Zone B; p = 0.007 in non-ABR). This gender difference persists after adjustment for location within the zone, consumption of meat derived from locally raised animals, age, body mass index, and smoking. There is no evidence for a gender difference in exposure, so variation in metabolism or elimination due to body fat or hormone-related factors may explain this finding. Elevated TCDD levels in women may contribute to adverse reproductive, developmental, and cancer outcomes.
Article: Cause specific mortality and cancer incidence among employees exposed to 2,3,7,8-TCDD after a 1953 reactor accident.[show abstract] [hide abstract]
ABSTRACT: To evaluate the long term health consequences of past occupational exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). Cancer incidence and cause specific mortality were examined up to and including 1992 in a group of 243 men with external comparisons and internal dose-response analyses. Model based estimates of TCDD dose (expressed in micrograms/kg body weight) were developed for all cohort members with an approach that incorporated detailed accounts of each employee's work activities, analyses of TCDD in blood lipid of 138 employees, and internally derived estimates of elimination rates of TCDD. The estimated dose of TCDD for 135 men was > or = 0.1 microgram/kg body weight and for 69 men > or = 1 microgram/kg body weight. Increased cancer risk ratios were found with higher doses of TCDD and longer interval since first exposure for all sites combined and digestive and respiratory cancers in particular. Within the high dose group (> or = 1 microgram/kg body weight), total cancer mortality was increased > or = 20 years after first exposure (13 cases, standardised mortality ratio (SMR) 1.97, 95% confidence interval (95% CI) 1.05-3.36) as was respiratory cancer (six cases, SMR 3.06; 95% CI 1.12-6.66). Among current cigarette smokers, 12 cancer deaths occurred in the high dose group (SMR 3.42, 95% CI 1.77-5.97) compared with seven deaths at lower doses of TCDD (SMR 1.29, 95% CI 0.52-2.66). Regression analyses based on the Cox's proportional hazards model provided further evidence of a relation between cumulative dose of TCDD and occurrence of both overall and digestive cancer. No evidence of an effect of TCDD on overall mortality or deaths due to circulatory disease was found and no cases of non-Hodgkin's lymphoma or soft tissue sarcoma have been found to date. Our findings are consistent with a carcinogenic effect induced by TCDD at doses > or = 1 microgram/kg body weight. With such a small cohort, the risk estimates are not very stable and could be affected by selection and confounding.Occupational and Environmental Medicine 10/1996; 53(9):606-12. · 3.02 Impact Factor
Article: Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans: the risks to human health. A review.[show abstract] [hide abstract]
ABSTRACT: 1 PCDDs and PCDFs are ubiquitous and persistent in the environment. They are to be found in body tissues of both humans and animals. 2 The most extensively studied PCDD is 2,3,7,8-TCDD. It has been shown to produce a wide range of effects and is considered to be a (non-genotoxic) carcinogen in animals. 3 Studies into the mechanisms of toxicity so far reveal that there is involvement of a specific receptor (Ah), however further work is required to elucidate the mechanisms of the various effects. 4 Reports on a number of human exposures to PCDDs and PCDFs are described. Results from human epidemiological studies are difficult to interpret: there have been problems in methodology; there has been inadequate information on intake, and exposures have often been to mixtures of PCDDs and/or PCDFs together with other related compounds. 5 Many regulatory authorities faced with the problem of providing an index of risk from exposure to mixtures of PCDDs and PCDFs have employed the concept of 'TCDD equivalents'. 6 Whether or not PCDDs and PCDFs pose a significant human health risk at current levels of exposure they remain of considerable interest to the toxicologist.Human toxicology 06/1989; 8(3):173-203.
Article: 2,3,7,8-Tetrachlorodibenzo-p-dioxin levels in adipose tissue of exposed and control persons in Missouri. An interim report.[show abstract] [hide abstract]
ABSTRACT: The compound 2,3,7,8-tetrachlorodibenzo-p-dioxin, commonly known as dioxin, was measured in the adipose tissue of 39 persons with a history of residential, recreational, or occupational exposure in Missouri and in 57 persons in a control group. All participants had detectable levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin in their adipose tissue, but the exposed group had significantly higher levels. Levels of six of the exposed persons were more than five times greater than the level of the highest control. Measuring 2,3,7,8-tetrachlorodibenzo-p-dioxin in adipose tissue provides a much improved index of exposure, an important advance for research studies evaluating the possible health effects of this compound.JAMA The Journal of the American Medical Association 11/1986; 256(19):2683-6. · 30.03 Impact Factor
2,3,7,8-Tetrachlorodibenzo-p-Dioxin Plasma Levels in Seveso 20 Years after
Maria Teresa Landi,1 2Dario Consonni,3 Donald G. Patterson, Jr.,4 Larry L. Needham,4 George Lucier,5 Paolo
Brambilla,6 Maria Angela Cazzaniga,6 Paolo MocarelliA6 Angela C. Pesatori,2'3 PierAlberto Bertazzi,Z3 and
Neil E. Caporaso1
1Genetic Epidemiology Branch, National Cancer Institute, Bethesda, MD 20892 USA; 2EPOCA, Epidemiology Research Center, University of
Milan, Italy; 31nstitute of Occupational Health, Istituti Clinici di Perfezionamento, Milan, Italy; 4Centers for Disease Control and Prevention,
Atlanta, GA 30341 USA; 5National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 USA; 6Desio Hospital,
University of Milan, Milan Italy
In 1976, near Seveso, Italy, an industrial accident caused the release oflarge quantities of2,3,7,8-
(TCDD) nto the atmosphere, resulting in the highest levels of the
toxicant ever recorded in humans. The contminated area was divided into three zones (A, B, R)
decreasing TCDD levels in soil, and a cohort incuding all residents was enu-
merated. The population of the surrounding noncontaminated area (notn-ABR) was chosen as
referent population. Two decade after the accident, plasmaTCDD level were measured in 62
subjects randomly sampled from the highest exposed zones (A and B) and 59 subjects from non-
ABR, frequency matched for age, gender, and cigarette smoking status. Subjects fliing in the
*exoed areas have persistently .elevated.plama TCDD levels (ran
mean _ 53.2 and 11.0 ppt for ZoneA anid Zone B,
distance from the accident site (p= 0.0001), down to general population values (4.9 ppt) in non-
ABR, thus vaidating the original zone classification based on.environmental measurements.
Womein have higherTCDD levels than men in the entirestudy area (p-0.0003 in Zone B;p -
0.007 in non-ABR). This gender difference persist after adjustment for location within the zone,
consumption of meat ived from loally raisdam, age, body mass index, and smoing.
There is no evidence for a gender di&rence in exposure, so variation in metabolism or elimina-
tion due to body fat or hormone-related factors mxiay exli
in women may contribute to adverse reproductive, developmental, and cancer outcomes. Key
work accident, dioxin, fat, gender, hormones, TCDD. Environ Health Penpec 106:273-277
(1998). [Online 31 March 1998]
1.2I89.9 ppt; geometc
ivel). Levels significantyd
this finding.Eleted TCDD levels
The Seveso accident occurred on 10 July
1976 when a reaction vessel in a local facto-
ry went exothermically out of control and
sent kilogram quantities of 2,3,7,8 tetra-
chlorodibenzo-p-dioxin (TCDD) into the
atmosphere. The doud of material was car-
ried southeast in a fan-shaped plume of fall-
out. Based on soil TCDD measurements,
the contaminated area was divided in three
zones (A,B,R) with progressively lower but
distinct contamination. Over the next few
weeks, chloracne developed in almost 200
local residents, and over the next several
weeks, the entire population of Zone A
(about 730 persons) was evacuated. To
investigate the possibility of long-term
health effects ofTCDD, a cohort, including
all the subjects ever living from the time of
the accident onward in Zone A (currently
around 800), Zone B (around 5,900), and
Zone R (around 38,000), was enumerated
and periodically updated. Approximately
232,000 subjects from the surrounding non-
contaminated area (non-ABR) were fol-
lowed to serve as a reference population for
mortality and cancer incidence studies (1).
TCDD is important because of its
broad toxicity in experimental animals and
humans (2, which includes teratogenic (3),
carcinogenic (4-7), hormonal (8,9),
immunologic (10), and possibly sex ratio
(11) effects. In addition, its persistence in
the environment and long half-life in
humans [estimated at 7 or more years
(12,13), and precisely at 8.2 years in the
Seveso population (14)], create an oppor-
tunity for chronic disease in humans and
long-term environmental consequences.
Seveso offers a unique opportunity to elu-
cidate these effects because the exposure
was relatively specific and substantial and
occurred over a wide dose range and in a
large and stable human population that
includes both genders and various age
A 15-year mortality study of the Seveso
population showed an increase in gastroin-
testinal cancer (particularly in females),
lymphatic and hematopoietic neoplasms,
and possibly soft tissue sarcoma (15). A 10-
year morbidity study showed similar find-
ings (in particular an increase of hepatobil-
iary cancer among females) and also
showed a slight decrease of breast and uter-
ine cancer incidence (16). Several studies
have detected a positive association of a
variety of cancers in other TCDD-exposed
populations (17-23), but other studies,
generally involving low exposures, have not
(24-28). However, most studies derive from
occupationally exposed groups, which
include mostly men, have potential exposure
to multiple occupational toxicants, and
involve chronic rather than acute exposure.
In addition, most of them lack a registry to
provide a framework for study. A compre-
hensive review of these studies can be found
in the recent IARC (International Agency
for Research on Cancer) Monograph on
polychlorodibenzo-para-dioxins and poly-
chlorinated dibenzofurans (29) in which
TCDD is defined as carcinogenic to
In this paper we present the distribution
of TCDD in the Seveso area, almost two
decades following the event.
Sixty-two subjects from the most TCDD-
contaminated zones (A and B) and 59 from
the noncontaminated area (non-ABR) were
studied. Subjects were randomly sampled
from the cohort and frequency matched by
gender, age, and cigarette smoking status.
Residence in the specific zone (A, B, or non-
ABR) was established by determining
address and verified by establishing actual
domicile (i.e., did the subject actually live at
the address corresponding to the legal
address?) and presence in the specified area at
the time ofthe accident. Subjects with severe
medical illness (liver, kidney, cardiac,
immune, neoplastic, or major psychiatric dis-
ease) were excluded through telephone calls
assisted by a physician. Exclusion rates were
low and similar across the zones (precisely,
five from non-ABR and four from zone B).
Informed consent was obtained from partici-
pants, and the study was reviewed and
approved by the local Institutional Review
Address correspondence to M.T. Landi, Genetic
Epidemiology Branch, EPN 400A, NCI/NIH, 6130
Executive Boulevard, Bethesda, MD 20892-7360
The authors are grateful for support from the
Region of Lombardy and Fondazione Lombardia
per l'Ambiente. We thank colleagues who reviewed
this work, including Bob Hoover, Patricia Hartge,
Margaret Tucker, and Carlo Zocchetti.
Received 17 September 1997; accepted 8 January
Environmental Health Perspectives
* Volume 106, Number 5, May 1998
Articles * Landi et al.
Board. A questionnaire including data on
demographics, lifestyle, foods consumed at
the time of the accident, residential history,
occupation, and reproductive and medical
history was administered by trained inter-
viewers. The dioxin assay was performed at
the Centers for Disease Control and
Prevention (CDC) using a high-resolution
gas chromatography/high resolution mass
spectrometric analysis performed on human
plasma, as described by Patterson et al. (30).
Specifically, we assayed for TCDD, other
dioxins, dibenzofuran congeners, and copla-
nar polychlorinated biphenyls (PCBs), with
results reported in parts per trillion (ppt),
lipid adjusted. Of 121 subjects, 11 samples
(4 from zone B and 7 from non-ABR) were
inadequate for analysis and were exduded.
Another 23 samples (9 from zone B and 14
from non-ABR) with valid but nonde-
tectable results had levels estimated by divid-
ing the lipid-adjusted detection limit by the
square root oftwo (31). Excluding or assign-
ing zero values for these samples did not
substantially change the reported findings.
Nonparametric tests (Wilcoxon rank-sum
and Kruskal-Wallis) for medians, and t- and
F-tests for geometric means were used in
univariate comparisons and in multiple
regression analyses. Geometric mean (GM)
and standard deviation (SD) values are
shown, unless otherwise specified.
Table 1. Characteristics of the study population by
zone and gender
Zone A Zone B Non-ABR Total
Mean age (years)
Mean weight (kg)
Mean height (cm)
Mean years living in
Abbreviatons: Non-ABR, noncontaminated area; BMI, body
mass index; PBF, percentage bodyfat F, female; M, male.
&Ever smoked cigarettes.
bM and F combined.
cDerived from BMI and normed for gender(39).
dThe Zone A population was evacuated and some people never
Characteristics of the study population are
shown in Table 1. There were 7 subjects
from Zone A (2 females, 5 males), 55 from
Zone B (28 females, 27 males), and 59
from non-ABR (32 females, 27 males).
The current mean TCDD levels in
individuals from Zone A, Zone B, and
non-ABR were 53.2 ppt, 11.0 ppt, and 4.9
ppt, respectively (p= 0.0001) (Table 2). If
we assume an 8.2-year half-life (14), the
extrapolated mean levels at the time of the
accident are 230.0 ppt for subjects from
Zone A and 47.5 ppt for residents of Zone
B (extrapolation is not relevant to the non-
ABR area, which was unaffected by the
accident). The absolute and extrapolated
median levels show a similar difference
across zones. All samples in Zone A had
detectable TCDD levels; when nine sam-
ples from Zone B with nondetectable
TCDD levels were excluded, the difference
across the zones persisted (extrapolated
mean in Zone B became 66 ppt).
Females from Zone B had significantly
higher plasma TCDD levels than did
males; 26 females had a mean of 17.6 ppt
compared to 25 males who had a mean of
6.7 ppt (p=0.0003). In non-ABR, females
also exhibited higher TCDD levels than
did males (means, 6.1 ppt and 3.7, respec-
tively; p=0.007) (Table 3). The highly sig-
nificant elevation in females was similarly
present when median levels were compared
using a ranking statistic (Zone B, p =
0.0003; non-ABR, p = 0.005). The small
numbers of subjects in Zone A precluded a
reasonable gender comparison. Besides
gender, no other variables were associated
with TCDD levels in non-ABR.
Based on analysis of a separate group of
Seveso subjects, a longerTCDD half-life has
been suggested in females (9.0 years, n= 15)
than men (7.1 years; n= 12) (L. Needham,
personal communication). When we extrap-
olated TCDD levels back to 1976, taking
into account the gender-specific half-lives,
the gender difference remained significant
(females, GM=66.8 ppt; males, GM=36.4
ppt; p=0.02, Zone B).
An increase in TCDD levels was found
in older subjects in Zone B (F-test, GM, p
= 0.03), most evident in individuals over
the age of 60 years. (Fig. 1). With fluctua-
tions due to small numbers, females had
higher levels than males in each age class
except for subjects over 70 years ofage.
As expected, the weight, height, and
body mass index (BMI) were higher in
males, while percentage body fat (PBF) was
higher in females (Table 1). Within gender
categories, TCDD levels were unrelated to
PBF, BMI, height, or weight. Reported
weight loss (Table 4) was weakly related to
TCDD levels in females only [no weight
loss (n=21;TCDD GM= 16.3; SD=2.1);
Table 2. Current and extrapolated TCDD levels (ppt) by zone
Abbreviations: Non-ABR, noncontaminated area; GM, geometric mean; GSD, geometric standard deviation.
fHalf-life,8.2 years (14).
bFTest for mean In(TCDO) difference among zones (current values).
CKruskal-Wallis test for median difference among zones (current values).
Table 3. TCDD Levels (ppt) by zone and gender
(p = 0.0003)b
Abbreviations: Non-ABR, noncontaminated area; F, female; M, male; GM, geometric mean; GSD, geometric standard
at-Test for mean ln(TCDD) difference between males and females.
bWilcoxon rank-sum test for median difference between males and females.
Volume 106, Number 5, May 1998
* Environmental Health Perspectives
Articles * Seveso, 20 years after
weight loss reported (n = 5; TCDD GM =
24.2; SD = 2.5; p = 0.30)]. There was no
association between amount of weight loss
andTCDD levels, after controlling for other
covariates (e.g., distance from the accident,
meat consumption, etc.). None ofthese fac-
tors, that is, higher BMI in men, explains
away the gender difference when using a
multivariate model including gender and
other covariates (Table 5).
When other variables were evaluated
(Table 4), only consumption of locally
raised meat at the time of the accident
retained an association with higher TCDD
levels, both in females (no meat, n = 15,
TCDD GM = 16.4 ppt, SD = 1.7; ate
meat, n = 11, GM = 19.3 ppt, SD = 2.8)
and in males (no meat, n = 16, GM = 4.8
ppt, SD = 2.3; ate meat, n = 9, GM = 12.1
ppt, SD = 1.0).
In a multivariate analysis of subjects in
Zone B (subjects from Zone A were exclud-
ed because of small numbers), we consid-
ered several variables and interaction terms
(e.g., gender and BMI, age and BMI).
None of these interactions significantly
contributed to TCDD variance. The final
model, based on factors plausible in our
study or reported in other TCDD-exposed
groups, included gender, distance from the
source within the zone (also taking into
account the course ofthe toxic doud imme-
diately after the accident), consumption of
locally produced meat, age, cigarette smok-
ing, and BMI (as an estimate ofPBF). Only
the first three variables were significantly
associated with measured TCDD levels
(Table 5). In a similar model, which also
included the gender-specific half-lives, the
gender difference remained statistically sig-
Among women in Zone B, oral contra-
ceptive users (n = 13; TCDD GM = 13.2
ppt; SD = 2.4) had lower levels than
nonusers (n = 13; GM = 23.4; SD = 1.7; p
= 0.05). In a multivariate model that also
included distance from the accident site,
age, BMI, and meat consumption, oral con-
traceptive use was significantly inversely
associated with TCDD levels (p = 0.04).
Adding parity to the model did not sub-
stantially change the result. When added to
the model, advanced age at menarche
exhibited a borderline association with
higher TCDD levels (p =0.07). This differ-
ence was unrelated to whether women
experienced menarche before or after the
accident. Other reproductive factors, e.g.,
age at menopause, were not associated.
Parity was not significantly associated with
TCDD levels, although the tendency was in
accord with expectations (parous, n = 20,
GM = 16.7 ppt, SD = 2.3 vs. nulliparous, n
=6, GM = 20.8 ppt, SD = 1.8).
We also measured current levels ofsome
PCBs, polychlorinated dibenzodioxins
(PCDDs), and polychlorinated dibenzofu-
rans (PCDFs) in the entire study area.
None of them varied across the zones, but
most of them (PCB126; 1,2,3,7,8-
CDF; 1,2,3,6,7,8-hectaCDF; 2,3,4,6,7,8-
hectaCDF) had significantly higher levels in
women and exhibited an age effect stronger
than forTCDD (data not shown).
Figure 1. Median TCDD levels (ppt) by gender and age in Zone B.
The numbers over each column indicate the number ofsubjectsin eachageandgender category.
This is the first study to confirm that ele-
vated TCDD levels persist in people from
the exposed areas almost 20 years after the
accident. Furthermore, mean TCDD levels
correspond to zone categorization based on
soil TCDD measurements determined in
1976 (1). Typical population values are
present in the surrounding non-ABR area.
Exceptionally high levels of TCDD have
been previously measured in serum speci-
mens drawn in 1976 from people who
were living in Seveso, particularly those
with chloracne (32, 33). These studies were
Table 4. TCDD levels (ppt) by zone, gender, and
Employed in 1976d
Knowledge of accidentd
Consumed locally grown vegetablesd
Consumed locally raised animalsd
Abbreviations: GM, geometric mean; Non-ABR, noncont-
&Subjects responding 'don't know or don't remember were not
included when totals fell short of 26 females and 25 males in Zone
B and 28 females and 24 males in non-ABR.
bPacks of cigarettes per year.
COnlytwosubjects drank no coffee.
dZone B only.
Environmental Health Perspectives * Volume 106, Number 5, May 1998
Articles * Landi et al.
Table 5. Multivariate model8 considering the relationship of measured TCDD doseb(ppt) to predictor vari-
ables in Zone B
Abbreviations: GM, geometric mean; F, female; M, male; BMI, body mass index.
'Each variable was adjusted forthe others in the model. Ofthe 51subjectsofZone B, 49 are included in the model because information on
distance from the accident sie within the zone was missing for 2subjects.
bDependent variable is measured ln(TCDD).
cZone B was divided into three areas according to the distance from the accident site and direction of the toxic cloud; 1 is the closest to the
dValues shown are ,.
0Currentlever/never smoking and smoking in 1976 (the time ofthe accident)were not associated with TCDD in other models.
focused on the potentially most highly
exposed residents. On the contrary, we
selected subjects randomly in order to have
a more representative sample of the general
population ofthe area. In this study group,
subjects with severe medical illness and pre-
vious chloracne were excluded.
We observed higher TCDD levels in
women in both univariate analysis and after
adjustment for other variables potentially
associated with TCDD. We consider expo-
sure to be an unlikely source for the gender
effect. First, presence in the area at the time
of the accident, number ofyears spent in the
zone, occupation, and distance from the acci-
dent site within the zone, did not explain the
gender difference. Second, if the difference
was solely due to some factor that favored
women being exposed to TCDD during the
accident, the effect should not be present in
the non-ABR area, which was unaffected by
the accident. We observed a significant gen-
der difference in the unexposed area, suggest-
ing that the effect does not specifically
depend upon the Seveso accident. We also
found higher levels of most dioxins, furans,
and PCBs in women of the entire area, sug-
gesting that the gender effect may be relevant
for a wider array of related compounds and
exposure settings. Finally, studies performed
on a separate group of exposed individuals
showed no hint of a gender difference at the
time ofthe accident (33).
A gender difference in TCDD metabo-
lism has been shown in rats (34), but the
mechanism underlining this difference is not
There is evidence that TCDD influ-
ences both male (8) and female (9) hor-
mones, but we are unaware of a hormonal
mechanism that can explain TCDD gender
differences. Evaluation of hormone-related
differences in TCDD metabolism is very
difficult because of the slow rate of metab-
olism. Oral contraceptive use was associat-
ed with lower TCDD levels. Oral contra-
ceptive use is known to reduce activity of
CYP1A2 (35), an enzyme that is involved
in estrogen metabolism (36) and is also
induced by TCDD. Neither of these estab-
lished effects of CYP1A2 provides a clear
mechanistic rationale for the oral contra-
Lactation is one of the few known
means of eliminating the highly lipophilic
dioxin from the body (37). Using parity as
a surrogate of lactation (the great majority
of women in the local region nurse their
children), we only observed a weak nega-
tive association of childbearing with
One mechanism that might contribute
to a gender difference is excretion of
TCDD via semen emission in men. Such a
mechanism might potentially account for
the lack ofa gender difference at older ages
in our study. However, in the only study
reported, to date, where TCDD levels were
determined in pooled semen from Vietnam
veterans (38), levels were relatively low [<5
parts per quadrillion (ppq), wet-weight],
suggesting that this mechanism is unlikely
to account for the difference observed in
this study. Given the relatively low serum
TCDD levels in the veterans study, an
investigation in subjects with higher expo-
sures would be more appropriate for assess-
ingTCDD excretion via semen.
Covariates that might influence the
half-life, based on literature reports
(12,13), include age and body fat. We
observed a weak effect of age on TCDD
levels, possibly due to declining steroid
hormones, TCDD excretion via semen, or
changes in body fat distribution or
amount. The reduction in the age effect
between the univariate (p = 0.03) and mul-
tivariate (p = 0.08) models suggests that
other factors are likely to contribute to the
association of age with TCDD. Body fat is
a plausible determinant ofthe gender effect
because higher TCDD levels in women
might be due to enhanced retention of the
lipid-soluble compound due to a greater
proportion of body weight as fat in
women. Women had higher PBF than
men; however, within each gender, PBF
was unrelated to TCDD levels. It was not
possible to include PBF and gender in the
same multivariate model because PBF is
gender normed (39). Including BMI alone
in the model does not influence the gender
effect. Ott and Zober (40) observed a rela-
tionship of PBF to half-life, with estimates
of 5.1 years in those with 20% body fat
and 8.9 years for 30% body fat. The failure
to observe a strong relationship between
PBF and TCDD levels in our study may
derive from the fact that in contrast to Ott,
we considered body fat at the time of the
study (i.e., 1993-1995) rather than at the
time of the original exposure (1976), even
though we controlled for weight loss.
Diet is likely to be a major route for
dioxin exposure in the general population
(41). Authorities prohibited consumption
of animals and vegetables from the conta-
minated area shortly after the accident, but
some residents may have been unaware of
or ignored these restrictions. In fact, we
found an association with meat consump-
tion, but it did not account for the gender
Smoking might influence the TCDD
level by CYP450 induction with a resultant
alteration in metabolism or as a marker for
hand-to-mouth activity, increased alcohol
intake, or changes in peripheral body fat. A
shorter TCDD half-life in smokers has
been suggested (13), but we found only a
weak relationship of pack-year history of
smoking to TCDD levels in females of
To our knowledge, a gender difference
has not been previously observed in
TCDD-exposed populations, perhaps
because most groups have consisted largely
ofmen exposed due to occupation or mili-
tary service, but at least one study that
induded a fewwomen has observed consis-
tent findings (42).
TCDD causes a dose-dependent
increase in hepatocellular carcinoma in
female but not male rats (43), and gender
differences in cancer occurrence have been
observed in Seveso (e.g., a significant
increase in hepatobiliary cancer in women
in Zone B) (16).
Volume 106, Number 5, May 1998 * Environmental Health Perspectives
Articles * Seveso, 20years after
The observed gender difference in
TCDD levels must be considered not only
in light of possible adverse effects in
women but also for developmental effects
in the offspring (44) exposed in utero as
well as via breast feeding. Given the myriad
biological effects of this environmental
contaminant, further research is needed to
determine whether a gender effect is pre-
sent in other groups exposed to TCDD or
related xenobiotics and to better under-
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Environmental Health Perspectives * Volume 106, Number 5, May 1998