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7
Reproductive Effects and Impacts
on Future Generations
This chapter summarizes the scientific literature published since Veterans
and Agent Orange: Update 2006, hereafter referred to as Update 2006 (IOM,
2007), on the association between exposure to herbicides and adverse reproduc-
tive or developmental effects. (Analogous shortened names are used to refer to
the updates for 1996, 1998, 2000, 2002, and 2004 [IOM, 1996, 1999, 2001, 2003,
2005].) The categories of association and the approach to categorizing the health
outcomes are discussed in Chapters 1 and 2. The literature considered in this
chapter includes studies of a broad spectrum of reproductive effects in Vietnam
veterans or other populations occupationally or environmentally exposed to the
herbicides sprayed in Vietnam or to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).
Because some polychlorinated biphenyls (PCBs) and polychlorodibenzofurans
(PCDFs) have dioxin-like biologic activity, studies of populations exposed to
PCBs or PCDFs were reviewed if their results were presented in terms of toxicity
equivalence quotients (TEQs).
As in previous updates, the adverse outcomes evaluated include impaired
fertility (in which endometriosis or declines in sperm quality may be involved),
increased fetal loss (spontaneous abortion and stillbirth) or neonatal and infant
mortality, and other adverse birth outcomes (including low birth weight, preterm
birth, and birth defects). In addition to the more delayed problem of childhood
cancer in their offspring, this update also addresses the concern of Vietnam vet-
erans that their military exposures may contribute to other problems that their
children experience later in life or are manifested in later generations.
To reduce repetition throughout the report, Chapter 5 presented design in-
formation on new studies that report findings on multiple health outcomes. To
provide context for publications that present new results on study populations
4
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46 VETERANS AND AGENT ORANGE: UPDATE 2008
that were addressed in publications reviewed in earlier updates, Chapter 5 also
discussed the overall characteristics of those populations with details about de-
sign and analysis relevant to individual papers. For new studies that report only
reproductive health outcomes and that are not revisiting previously studied popu-
lations, design information is summarized in this chapter with results.
This chapter’s primary emphasis is on the potential adverse reproductive
effects of herbicide exposure of men because the vast majority of Vietnam vet-
erans are men. However, about 8,000 women served in Vietnam (H. Kang, US
Department of Veterans Affairs, personal communication, December 14, 2000),
so findings relevant to female reproductive health are also included. Whenever
the information was available, an attempt was made to evaluate the effects of
maternal and paternal exposure separately. Exposure scenarios in human popula-
tions and experimental animals studied differ in their applicability to our popula-
tion of concern according to whether the exposed parent was a male or female
veteran. In addition, for published epidemiologic or experimental results to be
fully relevant to evaluation of the plausibility of reproductive effects in Vietnam
veterans, female as well as male, the timing of exposure needs to correspond
to the veterans’ experience (that is, occur only prior to conception). With the
possible exception of female veterans who became pregnant while serving in
Vietnam, pregnancies that might have been affected occurred after deployment,
when primary exposure had ceased.
BIOLOGIC PLAUSIBILITY OF REPRODUCTIVE EFFECTS
This chapter opens with a general discussion of factors that influence the
plausibility that TCDD and the four herbicides used in Vietnam could produce
adverse reproductive effects. There have been very few reproductive studies of
the four herbicides in question, particularly picloram and cacodylic acid, and
those studies generally have shown toxicity only at very high doses, so the pre-
ponderance of the following discussion concerns TCDD.
Because dioxin is stored in fat tissue and has a very long biologic half-life,
internal exposure at generally constant concentrations may continue after epi-
sodic, high-level exposure to external sources has ceased. If a person had high ex-
posure, there may still be high amounts of dioxin stored in fat tissue, which may
be mobilized, particularly at times of weight loss. That would not be expected to
be the case for nonlipophilic chemicals, such as cacodylic acid.
The paternal contribution to a pregnancy is limited to the contents of the
sperm that fertilizes an egg, any damage would be conveyed as DNA mutations
or epigenetic effects (that is, heritable changes in genome function that occur
without a change in primary DNA sequences). Dioxins have not been shown to
alter DNA sequences (they do not produce mutations), so the potential effects
in offspring are limited to epigenetic effects. Two possible mechanisms could
theoretically produce affected children: if sperm stem cells are altered by expo-
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REPRODUCTIVE EFFECTS AND IMPACTS ON FUTURE GENERATIONS
sure, they could continue to produce altered sperm; and mobilization of dioxin
from storage in adipose tissue (for example, due to weight loss) could continue
to damage a man’s developing sperm, and thus interfere with conception and
conceptuses. In any case, any exposure of the father that could affect his children
must occur before their conception.
Although ova, the maternal contribution to a conceptus, do not undergo the
repeated 90-day cycles of spermatogenesis, they might be damaged by modes of
exposure analogous to those affecting male gametes. In addition, at critical peri-
ods of gestation and even postnatally through breast milk, the female can mediate
exposure to the offspring as it develops. Such exposure can interfere with cell
replication, differentiation, and migration; with formation of tissues, organs, and
systems; and with structure. Dioxin in her bloodstream, whether from external
sources or released from fat stores, can cross the placenta and expose the develop-
ing embryo and fetus. Mobilization of dioxin during pregnancy or lactation may
be increased because the body is drawing on fat stores to supply nutrients to the
developing fetus or nursing infant. Breast milk has a high fat content, and the
concentration of dioxin in breast milk is about 100 times that in a mother’s blood.
In animal studies, TCDD crosses the placenta and is transferred via breast milk.
In humans, TCDD has been measured in circulating maternal blood, cord blood,
placenta, and breast milk (Suzuki et al., 2005), and it is estimated that an infant
breastfed for 1 year accumulates a dose of TCDD that is 6 times as high as that in
an infant not breastfed (Lorber and Phillips, 2002). Thus, the exposure of human
infants to TCDD in utero and via lactation has been demonstrated.
Toxicologists often distinguish between reproductive effects, which concern
the reproductive process itself, and developmental effects, which involve differ-
entiation of fetal tissues and maturation of the offspring. A connection between
TCDD exposure and human reproductive and developmental effects is, in general,
biologically plausible. However, more definitive conclusions about the potential
for such TCDD toxicity in humans are complicated by differences in sensitivity
and susceptibility among individual animals, strains, and species; by the lack of
strong evidence of organ-specific effects among species; by differences in route,
dose, duration, and timing of exposure; and by substantial differences in the
toxicokinetics of TCDD between laboratory animals and humans. Experiments
with 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic
acid (2,4,5-T) indicate that they have subcellular effects that could constitute a
biologically plausible mechanism for reproductive and developmental effects.
Evidence from animals, however, indicates that they do not have reproductive
effects and that they have developmental effects only at very high doses. There
is insufficient information on picloram and cacodylic acid to assess the biologic
plausibility of those compounds’ reproductive or developmental effects.
The biologic plausibility portions of sections on the specific outcomes con-
sidered in this chapter present more detailed toxicologic findings that are of
particular relevance to the outcomes discussed.
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48 VETERANS AND AGENT ORANGE: UPDATE 2008
ENDOMETRIOSIS
Endometriosis (International Classification of Diseases, 9th reision [ICD-9],
code 617) affects 5.5 million women in the United States and Canada at any given
time (NICHD, 2007). The endometrium is the tissue that lines the inside of the
uterus and is built up and shed each month during menstruation. In endometrio-
sis, endometrial cells are found outside the uterus—usually in other parts of the
reproductive system, in the abdomen, or on surfaces near the reproductive organs.
That misplaced tissue develops into growths or lesions that continue to respond to
hormonal changes in the body and break down and bleed each month in concert
with the menstrual cycle. Unlike blood released during normal shedding of the
endometrium lining the uterus, blood released in endometriosis has no way to
leave the body, and the results are inflammation, internal bleeding, and degenera-
tion of blood and tissue that can cause scarring, pain, infertility, adhesions, and
intestinal problems.
There are several theories of the etiology of endometriosis, including a ge-
netic contribution, but the cause remains unknown. Estrogen dependence and im-
mune modulation are established features of endometriosis but do not adequately
explain the cause of this disorder. It has been proposed that endometrium is
distributed through the body via blood or the lymphatic system; that menstrual
tissue backs up into the fallopian tubes, implants in the abdomen, and grows;
and that all women experience some form of tissue backup during menstruation
but only those with immune-system or hormonal problems experience the tissue
growth associated with endometriosis. Despite numerous symptoms that can
indicate endometriosis, diagnosis is possible only through laparoscopy or a more
invasive surgical technique. Several treatments for endometriosis are available,
but there is no cure.
Conclusions from VAO and Updates
Endometriosis was first reviewed in this series of reports in Update 2002,
which identified two relevant environmental studies, and Update 2004 examined
three environmental studies. Two additional environmental studies considered in
Update 2006 did not change the conclusion that the evidence was inadequate or
insufficient to support an association with herbicide exposure. Table 7-1 provides
a summary of relevant studies that have been reviewed.
Update of the Epidemiologic Literature
No new Vietnam-veteran or occupational studies addressing endometriosis
have been published since Update 2006.
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REPRODUCTIVE EFFECTS AND IMPACTS ON FUTURE GENERATIONS
TABLE 7-1 Selected Epidemiologic Studies—Endometriosis
Reference Study Population Study Results
ENVIRONMENTAL
New Studies
Heilier Serum DLC and aromatase No association between TEQs of DLCs in serum
et al., activity in endometriotic tissue and aromatase activity by regression analyses.
2006 from 47 patients in Belgium p-values = 0.37–0.90 for different endometriosis
subgroups.
Heilier 88 matched triads (264 total); Results for pelvic endometriosis vs controls
et al., patients with deep endometriotic Dietary fat: OR = 1.0 (95% CI 1.0–1.0)
2007 nodules, pelvic endometriosis, BMI: OR = 1.0 (95% CI 0.9–1.0)
controls matched for age, Occupation: OR = 0.5 (95% CI 0.2–1.1)
gynecologic practice in Belgium; Traffic: OR = 1.0 (95% CI 0.3–2.8)
routes of exposure to DLCs Incinerator: OR = 1.0 (95% CI 1.0–1.1)
examined
Tsuchiya 138 infertility patients in Japan; Results for advanced endometriosis
et al., laproscopically confirmed case– Total TEQ: OR = 0.5 (95% CI 0.2–1.7)
2007 control status, serum dioxin, PCB Genotype-specific: ORs = 0.3–0.6
TEQ; P450 genetic polymorphism No significant interaction between genotype,
dioxin TEQ
Studies Reviewed in Update 2006
Heilier Endometriosis in Belgian women 50 exposed cases, risk of increase of 10 pg/p lipid
et al., with overnight fasting serum of TEQ compounds: OR = 2.6 (95% CI 1.3–5.3)
2005 levels of PCDD, PCDF, PCB
Porpora Case–control study of Italian Mean total PCBs (ng/g)
et al., women with endometriosis, Cases, 410 ng/g
2006 measured serum PCBs Control, 250 ng/g
All PCB congeners: OR = 4.0 (95% CI 1.3–13)
Studies Review in Update 2004
De Felip Pilot study of Italian, Belgian Mean concentration of TCDD (ppt of lipid)
et al., women of reproductive age; Italy:
2004 compared concentrations of Controls (10 pooled samples), 1.6
TCDD, total TEQ in pooled Cases (two sets of six pooled samples), 2.1, 1.3
blood samples from women who Belgium:
had diagnosis endometriosis with Controls (seven pooled samples), 2.5
controls Cases (Set I, five pooled samples; Set II, six
pooled samples), 2.3, 2.3
Mean concentration of TEQ (ppt of lipid)
Italy:
Controls (10 pooled samples), 8.9 ± 1.3
(99% CI 7.2–11)
Cases (two sets of six pooled samples),
10.7 ± 1.6; 10.1 ± 1.5
Belgium:
Controls (seven pooled samples), 24.7 ± 3.7
(99% CI 20–29)
Cases (Set I, five pooled samples; Set II, six
pooled samples), 18.1 ± 2.7; 27.1 ± 4 .0
continued
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440 VETERANS AND AGENT ORANGE: UPDATE 2008
TABLE 7-1 Continued
Reference Study Population Study Results
Fierens Belgian women with Mean concentration of TEQ a (ppt of lipid)
et al., environmental exposure to Cases (n = 10), 26.2 (95% CI 18.2–37.7)
2003 PCDDs, PCDFs; compared Controls (n = 132), 25.6 (95% CI 24.3–28.9)
analyte concentrations in cases vs No significant difference
controls
Eskenazi Residents of Seveso Zones A Serum TCDD (ppt)
et al., and B up to 30 years old in 20.1–100 ppt (n = 8), OR = 1.2
2002 1976; compared incidence of (90% CI 0.3–4.5)
endometriosis across serum > 100 ppt (n = 9), OR = 2.1 (90% CI 0.5–8.0)
TCDD concentrations
Studies Reviewed in Update 2002
Pauwels Patients undergoing infertility Six exposed cases: OR = 4.6 (95% CI 0.5–43.6)
et al., treatment in Belgium; compared
2001 number of women with, without
endometriosis who had serum
dioxin levels up to 100 pg TEQ/g
of serum lipid
Mayani Residents of Jerusalem being Eight exposed cases: OR = 7.6
et al., evaluated for infertility; (95% CI 0.9–169.7)
1997 compared number of women with
high TCDD who had (n = 44),
did not have (n = 35) diagnosis of
endometriosis
ABBREVIATIONS: BMI, body mass index; CI, confidence interval; DLC, dioxin-like compound;
OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzodioxin; PCDF,
polychlorinated dibenzofuran; TCDD, 2,3,7,8-tetrachlorodibenzo- p-dioxin; TEQ, toxicity equivalent
quotient.
aTEQs calculated using the 1998 World Health Organization dioxin toxic equivalency factor (TEF)
method (Van den Berg et al., 1998).
Environmental Studies
Three new studies concerning exposure to the compounds of interest and
endometriosis have been conducted since the last update. The first two were
conducted by the same research group that reported an increased risk of endo-
metriosis with serum concentrations of dioxin-like compounds (DLCs) (Heilier
et al., 2005). In the new studies, they sought to expand their findings by focusing
on a possible biologic pathway (aromatase activity) and routes of exposure (such
as diet and residential proximity to waste incinerators). However, neither study
showed significant associations of endometriosis with the factors studied. The
third new study (Tsuchiya et al., 2007), which looked at specific genes in addi-
tion to dioxin exposure, did not find an association between dioxin exposure and
early stage-endometriosis regardless of genotype. In contrast with some earlier
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REPRODUCTIVE EFFECTS AND IMPACTS ON FUTURE GENERATIONS
studies, it found dioxin exposure to be associated with a lower risk of advanced
endometriosis. This lower risk was particularly strong in women who had a
specific genotype.
In the study of Heilier et al. (2006), 47 women admitted to a university
hospital in Belgium for the treatment of endometriosis agreed to participate in a
study aimed at determining whether aromatase activity was associated with the
concentration of DLCs in the endometriotic tissue. Aromatase is an enzyme im-
portant in the synthesis of estrogen, and drugs that block the synthesis of estrogen
lead to a reduction in endometriotic tissue. The authors thought that DLCs might
increase the aromatase, which would increase estrogen and lead to increased
growth of endometrial tissue. Endometriotic tissue was surgically removed from
the women, and DLCs and aromatase activity were measured in the laboratory.
They found that the concentration of DLCs was not associated with higher aro-
matase activity in endometriotic tissue.
Heilier et al. (2007) studied a total of 264 women in the same gynecologic
practice, divided equally into three groups matched on age; cases of pelvic
endometriosis, cases of deep endometriotic nodules, and controls. Serum TEQ
concentrations were available for 58 of these women who had participated in a
previous study by the authors (Heilier et al., 2005), which found a risk of endo-
metriosis associated with exposure to DLCs. Interviews conducted with patients
and controls collected information on diet, occupation, and residential proximity
to automobile traffic, waste incinerators, or other pollution sources. In the subset
of women whose serum DLCs were measured, they found that those with higher
concentrations were more likely to have consumed specific high-fat foods: pig
meat, marine fish, and fresh cream. However, neither dietary fat consumption,
body mass index (BMI), residential proximity to automobile traffic or waste
incinerators, nor specific occupation was associated with pelvic endometriosis
or with deep endometriotic nodules. The study used indirect measures of dioxin
exposure that are expected to be less precise than measures of serum dioxin, so
the results do not necessarily contradict those of their earlier study. The investi-
gators were unable to identify any likely source of dioxin exposure that differed
between cases and controls.
The third new study was conducted by Tsuchiya et al. (2007) in Japan to ex-
amine a possible association between genetic susceptibility to effects of exposure
to DLCs and endometriosis. They studied a total of 138 women who sought treat-
ment for infertility and had undergone laparoscopy. On the basis of laparoscopy,
the women were classified as having early-stage endometriosis (stages I–II), ad-
vanced endometriosis (stages III–IV), or no evidence of endometriosis (controls).
They measured serum dioxin and DLCs (TEQ per gram of lipids) and extracted
DNA from serum to determine polymorphisms (different genetic versions) of two
genes (cytochromes P450 [CYP] 1A1 and 1B1), which regulate the synthesis and
metabolism of endogenous and exogenous estrogens. They hypothesized that dif-
ferences in genetic makeup might confer differences in susceptibility to effects of
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442 VETERANS AND AGENT ORANGE: UPDATE 2008
DLCs and might explain why studies of endometriosis and dioxins show incon-
sistent results. Overall, serum-dioxin concentrations did not differ significantly
between cases with early or advanced endometriosis and controls (adjusted for
age). Women who had advanced endometriosis were less likely to have high
serum dioxins than controls (OR = 0.46, 95% CI 0.20–1.06), but the difference
was of borderline statistical significance; the result was virtually unchanged by
considering the total concentration of PCBs and dioxins. When genotype was
considered, the authors found no significant interaction between genotype and
serum dioxin in women who had early endometriosis. However, there was some
evidence of interaction between CYP genes and dioxin exposure with respect to
the risk of advanced endometriosis. There was a reduced risk of advanced endo-
metriosis after high dioxin exposure in women who had the less common allele
for CYP1A1, but the number of women in this group was very small. In summary,
the study found some evidence of a gene–environment interaction related to the
occurrence of endometriosis, but women who had higher concentrations of dioxin
were found to be at lower risk for advanced endometriosis.
Biologic Plausibility
Laboratory studies that used animal models and examined gene-expression
changes associated with human endometriosis and TCDD exposure provide evi-
dence to support the biologic plausibility of a link between TCDD exposure and
endometriosis. The first suggestion that TCDD exposure may be linked to endo-
metriosis came as a secondary finding from a study that exposed female rhesus
monkeys (Macaca mulatta) chronically to low concentrations of dietary TCDD
for 4 years (Rier et al., 1993). Ten years after the exposure ended, the investiga-
tors documented an increased incidence of endometriosis in the monkeys that
correlated with the dioxin exposure concentration. The small sample prevented
a definitive conclusion that TCDD was a causal agent in the development of the
endometriosis, but it led to numerous studies of the ability of TCDD to promote
the growth of pre-existing endometriotic lesions.
When fragments of uterine tissue were implanted in the peritoneal cavity to
mimic eutopic endometrial lesions, TCDD exposure was shown to promote the
survival and growth of the lesions in monkeys and in rodents (Cummings et al.,
1996; Johnson et al., 1997; Yang et al., 2000). In mice, direct treatment of endo-
metrial tissue with TCDD before placement into the peritoneal cavity resulted in
increased size and number of endometrial lesions (Bruner-Tran et al., 1999).
A number of proposed mechanisms by which TCDD may promote endome-
trial lesions provide additional biologic plausibility of the link between TCDD
and endometriosis. Human endometrial tissue expresses the aryl hydrocarbon
receptor (AHR) and its dimerization partner, the aryl hydrocarbon nuclear trans-
locator (ARNT) (Khorram et al., 2002), and three AHR target genes: CYP1A1,
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REPRODUCTIVE EFFECTS AND IMPACTS ON FUTURE GENERATIONS
1A2, and 1B1 (Bulun et al., 2000). That suggests that endometrial tissue is respon-
sive to TCDD. Furthermore, TCDD significantly decreases the ratio of progester-
one receptor B to progesterone receptor A in normal human endometrial stromal
cells and blocks the ability of progesterone to suppress matrix metalloproteinase
(MMP) expression; these actions may promote endometrial-tissue invasion. Both
the reduced ratio and the resistance to progesterone-mediated MMP suppression
are observed in endometrial tissue from women who have endometriosis (Igarashi
et al., 2005). Progesterone prevents endometrial breakdown before menstruation
by down-regulating expression of endometrial matrix metalloproteins during the
secretory phase of the menstrual cycle. Bruner-Tran et al. (2008) have proposed
that environmental toxicants, such as TCDD, that disrupt progesterone action may
predispose the endometrium to an inflammatory microenvironment that would
promote a process of tissue loss at menstruation. Their hypothesis is supported
by their evidence that TCDD inhibits expression of progesterone receptor and
transforming growth factor β2 in the endometrium and possibly expression of
other immune modulators regulated by progesterone.
TCDD induces changes in gene expression that mirror those observed in
endometrial lesions. For example, TCDD can induce expression of histamine-
releasing factor, which is increased in endometrial lesions and accelerates their
growth (Oikawa et al., 2002, 2003). Similarly, TCDD stimulates expression of
RANTES (regulated on activation, normal T cell–expressed, and secreted) in
endometrial stromal cells, and RANTES concentration and bioactivity are in-
creased in women who have endometriosis (Zhao et al., 2002). The two CC-motif
chemokines (chemotactic cytokines), RANTES and macrophage-inflammatory
protein (MIP)-1α, have been identified as potential contributors to the pathogen-
esis and progression of endometriosis. To probe the effect of dioxin exposure and
estrogen on expression of those chemokines in endometriosis-associated cells
and to explore the pathogenesis of endometriosis, endometrial stromal cells were
exposed to a combination of 17β-estradiol and TCDD. The combined treatment
increased the secretion of RANTES and MIP-1α, promoted the invasiveness of
endometrial stromal cells, and increased the expression of matrix metallopro-
teins MMP-2 and MMP-9 in endometrial stromal cells, indicating that combined
TCDD and estradiol may facilitate the onset of endometriosis and contribute to
its development by increasing the invasion of endometrial stromal cells medi-
ated by CC-motif chemokines (Yu et al., 2008). Those data are consistent with
the evidence of an interaction between the AHR and the estrogen receptor that
induces estrogen-mediated proliferative effects in the mouse uterus (Ohtake et al.,
2008). Differences between the mouse uterus and the human endometrium pre-
vent absolute extrapolation, but the data suggest that dioxins may induce changes
in endometrial physiology. In summary, it may be expected that TCDD exposure
would create an inflammatory endometrial microenvironment that could disrupt
endometrial function and cause disease.
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444 VETERANS AND AGENT ORANGE: UPDATE 2008
Although those studies do not establish the degree to which TCDD may
cause or promote endometriosis, they do provide evidence that supports the bio-
logic plausibility of a link between TCDD exposure and endometriosis.
Synthesis
The three new studies described above were designed to follow on previous
studies showing an association between DLCs and endometriosis. Two of the
studies (Heilier et al., 2006, 2007) were conducted by the same research group
that had found a significant association between blood concentrations of DLCs
and risk of endometriosis. They sought to shed light on possible biologic path-
ways and routes of exposure that might expand on the previous findings. How-
ever, neither the evaluation of an enzyme important in the synthesis of estrogen
nor examination of routes of exposure to dioxin yielded evidence of association
with endometriosis. The third new study (Tsuchiya et al., 2007) found a decreased
risk of endometriosis in women with higher dioxin concentrations.
Overall, the studies linking dioxin exposure with endometriosis are few in
number and inconsistent. The association in animal studies is biologically plau-
sible, but it is possible that human exposures are too low to show an association
consistently.
Conclusion
On the basis of the evidence reviewed here and in the previous VAO reports,
the committee concludes that there is inadequate or insufficient evidence to sup-
port an association between exposure to the chemicals of interest and human
endometriosis.
FERTILITY
Male reproductive function is under the control of several components whose
proper coordination is important for normal fertility. Several of the components
and some health outcomes related to male fertility, including reproductive hor-
mones and sperm characteristics, can be studied as indicators of fertility. The
reproductive neuroendocrine axis involves the central nervous system, the an-
terior pituitary gland, and the testis. The hypothalamus integrates neural inputs
from the central and peripheral nervous systems and regulates the gonadotropins
luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Both are se-
creted into the circulation in episodic bursts by the anterior pituitary gland and are
necessary for normal spermatogenesis. In the testis, LH interacts with receptors
on Leydig cells, where it stimulates increased testosterone synthesis. FSH and
the testosterone from the Leydig cells interact with the Sertoli cells in the semi-
niferous tubule epithelium to regulate spermatogenesis. More detailed reviews
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REPRODUCTIVE EFFECTS AND IMPACTS ON FUTURE GENERATIONS
of the male reproductive hormones can be found elsewhere (Knobil et al., 1994;
Yen and Jaffe, 1991). Several agents, such as lead and dibromochloropropane,
affect the neuroendocrine system and spermatogenesis (for reviews, see Bonde
and Giwercman, 1995; Tas et al., 1996).
Studies of the relationship between chemicals and fertility are less common
in women than in men. Some chemicals may disrupt the female hormonal bal-
ance necessary for proper functioning. Normal menstrual-cycle functioning is
also important in the risk of hormonally related diseases, such as osteopenia,
breast cancer, and cardiovascular disease. Chemicals can have multiple effects
on the female system, including modulation of hormone concentrations result-
ing in menstrual-cycle or ovarian-cycle irregularities, changes in menarche and
menopause, and impairment of fertility (Bretveld et al., 2006a,b). In this section,
we also discuss studies that have focused on menstrual-cycle characteristics
and age at menarche or menopause. An affect on age at menarche would be of
concern among the daughters of Vietnam veterans rather than among female
veterans themselves, but the occurrence of this effect in other populations would
demonstrate the ability of the chemicals in question to perturb functioning of the
female reproductive system.
Conclusions from VAO and Updates
The committee responsible for the original VAO report (IOM, 1994) con-
cluded that there was inadequate or insufficient evidence of an association be-
tween exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and altered
sperm characteristics or infertility. Overall, additional information available to
the committees responsible for Update 1996, Update 1998, Update 2000, Update
2002, Update 2004, and Update 2006 did not change that finding. Reviews of the
relevant studies are presented in the earlier reports. Tables 7-2 and 7-3 summarize
the studies related to male and female fertility, respectively.
Update of the Epidemiologic Literature
Male Fertility
Vietnam-Veteran Studies One new Vietnam-veteran study has been published
since Update 2006. Gupta et al. (2006) compared serum testosterone concentra-
tions measured in 1987 with TCDD concentrations measured at the same time in
veterans in the Air Force Health Study. A total of 971 Ranch Hand veterans and
1,266 comparison veterans with serum TCDD and serum testosterone measure-
ments were included in the analyses. After adjustment for age and BMI in 1987
and for a percentage change in BMI from the end of their Southeast Asia tour
to 1987, higher serum TCDD was significantly associated with lower testoster-
one concentrations in both Ranch Hands (slope for ln[TCDD] = -0.02, 95% CI
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