5. Effects on humans
The human endocrine system controls various biofunctions via complex
mechanisms. Disrupting this system can result in a variety of health effects.
Thus far, there have been no reports on definite causal relations between healtheffects on humans and endocrine disruptors, excluding instances caused bydiethylstilbestrol (DES) which have been for possible pharmacological actions on
the endocrine system.
On the other hand, investigations on wildlife and some epidemiologicalinvestigations on humans have revealed many types of diverse effects on thefemalereproductive

system,male

reproductive

system,thyroid

gland,

hypothalamus, and pituitary gland. It is feared that these chemicals can generate
negative effects on not only the parent generation directly exposed to them, butalso the next generation. These effects include endometriosis, uterine cancer,
breast cancer in women, and prostate cancer, testicular cancer, decreased sperm
count, and hypospadias in men.
The paragraphs below outline these effects. However, there are many aspects leftto elucidate, including causative substances, the environment, and mechanisms. If
any relationship between these effects and possible endocrine disruptors areindicated, it will be necessary to conduct animal studies and to determine details
such as the types of chemicals and the severity of effects, .

(1)(1) Effects on the female reproductive system and mammary glands
1.

Uterine cancer
Uterine cancer can be divided into carcinoma of the uterine cervix andcarcinoma of the uterine body, but the latter is closely related to hormones.
There are approximately 12,000 cases of uterine cervix cancer a year in Japan(estimated for 1990), but thus is thought not to be closely related to hormones.
There are approximately 3,000 cases of uterine body cancer a year in Japan(estimated for 1990), and although the incidence of uterine cervix cancer isdecreasing, the age-standardized incidence of uterine body cancer is increasing.
Internationally, however, the incidence of uterine body cancer in Japan is lessthan half that of the U.S. and Europe.

23

The risk factors of uterine body cancer are similar to those of breast cancer, andinclude duration of menstruation, childbirth and obesity, which affectendogenous hormone levels. In addition, estrogen supplementary therapy after
menopause and female hormone compounding agents of estrogen-progestogensequential use are known to increase the risk of uterine body cancer*18. In the
U.S., the incidence of uterine body cancer after menopause increased from thelatter half of the 1960’s, but begun to decrease from the mid 1970’s. It has beensuggested that this decrease is linked to the spread of hormone supplementary
therapy using only estrogen, and the switch to combination therapy withprogestogen. In women who used drugs containing female hormones (i.e.
estrogen and progestogen in combination), the risk reportedly decreased byabout 50% compared to those who did not use the drugs*18. That is, whenprogestogen is administered concomitantly, the risk of uterine body cancer isdecreased via the suppression of uterine gland cell proliferation. There is little
literature on the effect of chemicals suspected of endocrine disruption, but mostof these chemicals reduce the risk of uterine body cancer; as to dioxin, one
theory holds that its effects are due to its anti-estrogen action*19.
The administration of tamoxifen, which is known to reduce the risk of breast
cancer, was found by randomized controlled trial to increase the risk of uterine
body cancer*20.
2.

Endometriosis
The number of reported cases with endometriosis is on the increase due to theimprovement of medical care technology and probably also due to actual
increase in incidence.

The causes of endometriosis remain to be unclarified,

but are thought to be multi-factorial. Based on studies in humans, it is clearthat estrogen is needed for the development and progress of endometriosis.
However, it does not necessarily play a decisive role in the etiology ofendometriosis in that no apparent abnormality in estrogen secretion isassociated with endometriosis.
In a study using a small number of rhesus monkeys, the relation between
exposure to dioxin and endometriosis has been suggested*21.

However, a

recent study using rhesus monkeys, indicated that polychlorinated biphenyl

24

(PCB) at as a ten times higher concentration, (standardized by dioxin) as thatused in the previous study does not induce endometriosis*22.
In humans, dioxin was reportedly detected in the blood of 8 of 44 infertile
women with endometriosis, whereas it was detected in 1 out of 35 infertile
women without endometriosis, indicating a higher dioxin detection rate inpatients with endometriosis*23. On the other hand, Canadian research has
recently reported no difference in plasma concentrations of total organic
chlorine compounds, including dioxin, between 86 patients with endometriosis
and 70 control cases*24.

At this moment, information and knowledge areinsufficient regarding any link between endometriosis and endocrine
disruptors.
At present, a continuing study is under way in Seveso, Italy on women exposed
to TCDD.

Further research must be promoted to elucidate the relation

between endocrine disruptors and endometriosis.
3.

Breast cancer
Breast cancer occurs at highest incidence in women in their late 40’s and intheir 60’s, the age distribution of breast cancer having two peaks.

In Japan,there are approximately 27,000 cases a year (estimated for 1992), and the agestandardized incidence is increasing.

The incidence of breast cancer is low inJapan, at less than half that of the U.S. and Europe. However, in Japanese
who have moved to the U.S., breast cancer has increased at a higher rate thanthe comparable rate in Japan, which suggests its relation with radical changes
in eating habits.
The risk factors for breast cancer include early menarche, late menopanse, latechildbirth, nulliparity, obesity and diet (excess calories, few vegetables), factorsthat affect endogenous hormone levels.

The increasing trend of breast cancer

in Japan, and the regional differences seen internationally, can in part be
explained by these factors.

It has been reported that post-menopausal

supplementary therapy using hormone preparations may increase the risk
because of the delay of menopausal age for the period the estrogen is used, so ahigh concentration of estrogen in the body may be closely related to thedevelopment of breast cancer, by promoting proliferation of mammary gland25

cells.
The generally used female hormone compound agents contain progestogen andestrogen, but not all researchers agree that they increase the risk of breast
cancer.

The amount of hormones, the type of hormone preparation used,period of use, when used (before or after menopause) and features of the user
(family history of breast cancer, nulliparity) seem to have different effects. In
regard to DES, which was used during the 1940’s to prevent miscarriage, its
etiological relation with vaginal clear cell adenocarcinoma during puberty andadolescence in daughters born from women using the chemical has been
established, but the risk of breast cancer is reportedly increased by about 30%
in the mothers themselves, as evidenced in randomized controlled trial
participants and follow-up study on users*25.

On the other hand, a recent

randomized controlled trial has confirmed that in women without breast cancer,
continuous administration (over several years) of the breast cancer treatment
drug tamoxifen, which binds with estrogen receptors in competition withestrogen, decreases the risk of breast cancer*20. It has also been suggested
that phytoestrogen contained in soy beans decreases serum estrogenconcentrations and decreases the risk of breast cancer, which fact may berelated to the small number of breast cancer cases in Japan*26.
In regard to endocrine disruptors, since their main actions are estrogenic andanti-estrogen, it has been suggested that they may have some effect on thedevelopment of breast cancer.

Various epidemiological studies have been

conducted regarding the relation between breast cancer and exposure tochemicals suspected of endocrine-disrupting effects, such as chlorine pesticides(DDT and its metabolite DDE), dioxins (especially TCDD), which are
combustion byproducts, and polychlorinated biphenyls (PCBs), which areindustrial byproducts.

Follow-up studies on women highly exposed to TCDD

and PCBs professionally, and studies on comparison of DDE and PCB in fatty
tissues and serum among patients and controls have been reported, but
information and knowledge actively supporting their relation have not yet beenobtained*19.
As per the above, in regard to pharmaceuticals synthesized to have estrogenic
actions in themselves, they may increase the risk of breast cancer relative to26

dosage and period of use, but there is little evidence that environmental low
dosage exposure to endocrine disruptors exerting estrogenic action is a risk
factor for breast cancer in Japan; the possibility is thought to be low at present.
4.

Others
It is known that exposure of a female fetus to DES increases the risk ofcongenital uterine anomaly, and the later development of vaginal cancer. DES
is a strong synthetic estrogen preparation, and was used in the past as a drug
to prevent miscarriage.

It used to be administered to treat breast cancer, but

presently is not clinically used for this purpose.
DES may be considered an endocrine disruptor in the broad sense, but
although many other substances indirectly affect hormone actions, this is thestrongest estrogen preparation; the above abnormalities due to thispreparation are thought to result from receiving inappropriate estrogen
exposure in utero.

That is, this can be viewed as a pharmacological action of

estrogen to the fetus, and not the specific action of DES. Among the chemicals
occurring in the environment, no other substance has estrogenic property as
strong as DES; since the prohibition of DES use, DES-associated abnormalities
no more come about.

(2)(2) Effects on the male reproductive system
Certain kinds of chemicals are reported to have estrogenic actions or antiandrogenic actions on experimental animals and to cause abnormalities in themale reproductive system, such as in reduced spermatogenesis ability andreproductive-duct abnormalities. These results from animal experiments invite
concerns that these chemicals can have various adverse effects, such as a decline
in sperm count and an increase in the incidence of prostate cancer in humans.
Several studies have been conducted on humans. Observations on males exposed
to DES as fetuses have revealed that (1) disrupting actions of exogenous estrogenon the reproductive system during the developmental period were weaker thanthose in rodents, and (2) there was no rise in the incidence of cancer in the male
reproductive system. Below are the suspected major health effects of chemicals on
humans.

27

1.

Decline in sperm countIn 1993, Sharpe and Skakkebaek*27 reported in The Lancet their hypothesisthat reproductive anomalies such as decline in sperm count, testicular cancer,
hypospadias, prostate cancer and male infertility are increasing in relation to
estrogen in the environment.

In 1993, Colborn et al.*28 also took up 63

chemicals regarded as having endocrine-disrupting actions similar to estrogenactions, and the number of such chemicals is increasing.

Representative

chemicals include DDT, PCBs, nonyl phenol used in synthetic detergents,
bisphenol A and phthalic acid ester used in the plastic materials andplasticizers, styrene contained in Styrofoam, and dioxin, which is generated in
the process of industrial production and in the incineration of garbage.
Steroid hormones used as pharmaceuticals and natural phytoestrogen havealso been listed as chemicals thought to exert endocrine-disrupting actions.
In regard to their effects on human sperm, there have been reports on sperm
count decline due to fetal DES exposure, professional exposure to pesticides
and other substances, and dioxin exposure in veterans of the Vietnam War,but there have been reports disputing these as well*29*30.

Moreover, allinstances of established effects of endocrine disruptors on humans have
involved accidental exposure. Currently, there are no reports of endocrine
disruptors within the general living environment causing declines in humansperm count, decrease in the quality of semen or abnormalities in the
reproductive organs.
In regard to the human sperm question, at present there is not enoughinformation as to methodology, nor enough basic knowledge. Although there
is a need for comparisons according to age, time changes and regional
differences, even standards for seminal findings in healthy Japanese males
have not been accurately established.
Under these circumstances, an international joint research project wasorganized in 1997 by Skakkebaek et al. to study the reproductive functions ofnormal males.

Investigations are now under way in Denmark, Finland,

Scotland, France, Japan and other countries, and are scheduled to begin in the
U.S. this fall.

In Japan, Iwamoto’s group is conducting an investigation in28

the Kawasaki-Yokohama region from November 1997.

Investigations onregional differences are scheduled to begin in a number of areas all over Japan
at the end of this year. Reproductive functions are the keys to survival of a
species, not only humans but all living beings.

Possible effects on

reproductive functions, as long as they are suspected, should be regarded withthe highest priority regardless of whether there is concrete evidence, and nomatter what the cause might be.
a)

Background of problems with sperm counts

In 1974, Nelson and Bunge of the U.S. reported that the average sperm countof 386 males before vasectomy for contraceptive purposes was unexpectedly
low (48 × 106/ml) compared to that of cases reported before (more than 100
× 106/ml in many cases), and hypothesized that some kind of environmental
factor was involved*31.

MacLeod of Cornell University in the U.S., who wasan authority on sperm*32, criticized this study, and a report in 1979 on an
investigation conducted on more than 15,000 males over a period of ten years
concluded that there was no decreasing trend in sperm count.

This settled

the controversy at the time, and although there were subsequent reports on
the decrease in sperm quality, this controversy did not reemerge until the
1990’s.
Skakkebaek, on the other hand, who had been researching testicular cancer at
the University of Copenhagen, learned from statistical investigations that theincidence of testicular cancer had increased by three to four times in
Scandinavia during the past 50 years. From several researches, almost all
cancer registries in the Western World have noted a remarkable increase intesticular cancer. Focusing on the relation of this finding with the reported
increase of abnormalities in male reproductive organs, such as cryptorchidism
and hypospadias, he began tackling this issue by organizing a team.

To

investigate whether semen quality has changed during the past 50 years, hisgroup attempted to examine past scientific literature from around the world,
to find data on sperm counts in healthy males. The results, reported in the

British Medical Journal by Carlsen et al.*33, were shocking, as it revealed thatthe human sperm count had halved in 50 years.

Immediately after, manystudies from various countries followed, reporting on the decline in sperm
count and the decrease in semen quality.

29

Not only were these studies

introduced in medical journals; the general mass media also rushed to takethem up. The report by Carlsen et al. thus caused a sensation; but at thesame time it was harshly criticized. Faults in the selection standards of thequoted literature and statistical analysis methods were pointed out, andactual investigations denying a decrease in semen quality followed. Recently,
along with such negative reports, have come reports that there has indeed
been a decrease in semen quality, so this controversy is still ongoing.

At thesame time, attempts are under way to reinvestigate this matter.
b)

Reports concluding that sperm counts are decreasing

Carlsen et al. reported that the average sperm concentration decreased by
42%, from 113 × 106/ml in 1940 to 66 × 106/ml in 1990, and that the
average semen volume decreased significantly, from 3.40 ml to 2.75 ml.
Auger et al.*34 reported that as a result of investigating 1,351 Parisianapproved sperm donors aged 19 to 59 years from 1973 to 1992, sperm
concentration decreased by 2.1% a year, from 89 × 106/ml in 1973 to 60 ×106/ml in 1992, that motile sperm count and with sperm count normal
morphology also significantly decreased, and that in younger generations,sperm concentration, motility rate and normal sperm morphology rate
decreased significantly.

They concluded that in these males there was adecrease in semen quality. Van Waeleghem et al.*35 reported from Belgium,in an investigation over the past 19 years on the semen of 416 candidate
sperm donors aged 20 to 40 years, that sperm concentration decreased by 12.6
× 106/ml, but that there was no change in sperm count per ejaculation.
Furthermore, when the periods 1977 - 1980 and 1990 - 1995 were compared,
the normal sperm morphology rate was seen to decrease from 39.2% to 26.6%
and forward sperm motility rate to decrease from 52.7% to 31.7%.

Irvine etal.*36 compared before 1959 and after 1970 in Scotland, and indicated thatsperm concentration declined from 98 × 106/ml among donors born before
1959 to 78 × 106/ml among donors born after 1970.

Ginsburg et al.*37

compared the periods 1978 - 1983 and 1984 - 1989, and reported that sperm
concentration decreased from 101 × 106/ml to 96 × 106/ml.
c)Reports indicating that sperm concentrations are not declining but rising

In 1979, MacLeod et al.*32 studied the time-related change in sperm

30

concentration from 1966 to 1977, but as there was no decreasing trend in
sperm concentration or seminal fluid volume, concluded that sperm
concentration had not decreased since 1951 when they gave their first report.
Fisch et al.*38 conducted a comparative study of three areas in the U.S. during
the period from 1970 to 1994, and found that sperm concentration andmotility rate were 72.7 × 106/ml and 51.4%, respectively, for California,
which was the lowest, followed by 100.8 × 106/ml and 56%, respectively, for
Minnesota and 131.5 × 106/ml and 58.2%, respectively, for New York, which
was the highest.

Their research showed that there were significant

differences among the three areas, but concluded that the sperm count overthe past 25 years had not decreased in these areas.

Paulsen et al.*39, in an

investigation in Seattle, reported that there was no decline in sperm countfrom 1972 to 1993. Bujan et al.*40 reported no decline in sperm concentration
during a 20-year period from 1972 to 1992 in the Toulouse, France. A reportfrom Israel in 1997*41 concluded that there was no change in sperm
concentration and motility rate from 1980 to 1995.
d)

Reports from JapanThe first report in Japan on normal male sperm count was that by Takashima
et al.*42 in 1954, when it was 57.6 × 106/ml.

In 1982, Yoshida*43 reported,

based on an investigation for two years from 1976, that the average seminal
fluid volume was 3.0 ml and that the average sperm concentration was 106 ×
106/ml, excluding one case of azoospermia. In 1984, Ikegaki et al.*44 reported
that sperm concentration was 70.9 × 106/ml, based on an investigation forfive years from 1975.

Recently, Oshio et al.*45 reported that in a study on

those in their 20’s and 40’s, the average sperm concentration was 45.8 ×106/ml and 78.0 × 106/ml, respectively, and that the average motility rate
was 27.2% and 28.0%, respectively, and pointed out the decline in sperm countand motility rate for those in their 20’s.

Iwamoto et al. reported in researchon partners of pregnant women that the average sperm concentration was
82.6 × 106/ml and motility rate was 54%, and Yoshimura et al.*46 reported
that time changes in seminal findings indicated a decline in sperm count, but
further analysis is awaited.
e)Problems regarding human sperm studies

31

Seminal findings can change pathologically, as well as physiologically, due tovarious factors. In much of the past literature, the abstinence period was notconstant.

The collection of semen through masturbation is affected byvarious problems, such as repetition.

When semen was submitted a numberof times, there have been studies that used only the first results or the best of
several results. Results may also change according to the technical expert
conducting the test.

Measurements by automatic sperm analyzers vary

according to the equipment, which is not a problem with relative changes
within the findings, but data obtained using different equipment cannot bestrictly compared.
Fisch*38 reanalyzed the regional diversity of the data by Carlsen et al.*33, andshowed that the average sperm concentration differed greatly according toregion, and that much of the research done initially contained much data fromNew York, which had a high concentration, suggesting that regional
inclinations had disproportionately increased the levels of early data.

It hasbeen often reported that data from New York show high sperm concentration,
but the reason for this is not known.

In regard to changes in sperm count,before considering whether or not there is a real decline worldwide, it isnecessary to focus on the changes in a specific area.

This is because semenquality may be decreasing in one area but not in another. The problem ofregional differences is often regarded as a factor distorting analysis results,
but the fact of regional differences in semen quality is in itself an interesting
phenomenon.

The question of regional differences must be addressed fromthe aspect of genetic factors, as well as environmental factors.
2.

Prostate cancer
Prostate cancer develops in men over 50 years old; there are approximately
9,000 cases a year (estimated for 1992) in Japan.

The age-standardized

incidence tends to be increasing, but internationally the incidence in Japan isabout 10 to 20% that of the U.S. and Europe.

In Japanese who have moved to

the U.S, the incidence has clearly increased, and its relation with changes in
dietary habits has been pointed out. The radical increase in incidence seenfrom the latter part of the 1980’s in the U.S is thought to be due to theincrease in number of cases discovered by the spread of prostate cancer
screening methods, such as serum PSA (prostate-specific antigen), and by32

palpation; prostate cancer incidence is recently decreasing.

There are no

established risk factors for prostate cancer, but factors that affect the levels ofendogenous hormones (testosterone, etc.), such as diet (high intake of fats andred meats, low intake of vegetables) and sexual activity have been suggested,
and it is thought to be a hormone-related cancer.
In regard to prostate cancer’s relation with chemicals suspected of having
endocrine-disrupting actions, a follow-up study of a small number of people
professionally exposed to such chemicals, as for example, by spraying of
herbicides, or from coke oven exhaust, showed a risk increase*47, but there has
been little epidemiological research and there is little information compared tothe amount available concerning breast cancer.
3.

Testicular cancer
Testicular cancer develops in young males in their 20’s to 30’s, and it has apeculiar age-related characteristic.

In Japan, the incidence is approximately

800 patients a year (estimated for 1992), and although the age-standardized
incidence is based on a small number and is unstable, it shows a tendency toincrease.

In the U.S. and Europe, it formerly tended to increase in all

countries, but recently has leveled off or is decreasing.

In the U.S., theincidence differs among ethnic groups by about five times, with no increase
seen for black males, who have a low incidence.

The incidence in Japan isremarkably low compared to that of the U.S. and Europe, as with otherhormone-related cancers.

As the risk factors of testicular cancer,

cryptorchidism related to low androgen conditions has been established, andreportedly increases risk by about two to ten times*48.

The relation withmaterial estrogen preparation use during early pregnancy has been reported
in a small number of cases, but in a follow-up study of 250 boys born ofpregnant women receiving DES or placebo, there was no case of testicularcancer in either group*30.
There are not many reports on testicular cancer’s relation with chemicals
suspected of endocrine-disrupting actions. Some studies show that while thedisease is increasing in incidence in Scandinavian countries, DDE
concentration in breast milk has been decreasing since around 1970, and that33

despite similar levels of DDE in breast milk for the four Scandinavian
countries, there are regional differences in testicular cancer incidence, with afactor of four*49.

In light of these studies, it is thought that there is little

relation between DDT and testicular cancer.
4.

Hypospadias
Hypospadias is a congenital anomaly of a relatively high incidence amongurological diseases in boys.

It originates in incomplete fusion of thelabioscrotal fold in morphogensis of the external genitalia of the fetus fromabout 8 to 12 weeks, and results in an abnormal opening of the urethra in theventral penis or scrotum.

Development of the external genitalia depends on

the testosterone (T) secretion of the fetal testicles.
The cause of this condition is still unknown, but it is thought to be due to theinteraction of factors including those of the mother, such as first childbirth orlate childbirth; environmental factors, such as fetal exposure to mutagens,and genetic factors.

Clinical research has shown that there are cases inwhich the patients lack T metabolites and T receptors.

Hypospadias isthought to result from abnormalities of endocrine that affect the developmentof male reproductive organs.
Reports on trends in the incidence of hypospadias show that the condition
tended to increase in the 1980’s compared to the 1970’s in Norway*50,
Sweden*51, Denmark*52, the U.K.*53 and Hungary*54. According to the reportby Matlai et al.*53, it increased in England and Wales; in Hungary*51 itincreased from 12 to 24 per 10000 births in a comparison between 1971 and
1983.

In Sweden, Kallen et al.*55 reported that hypospadias increased from 8

to 12 per 10000 births from 1965 and 1979, but this increase occurred from1969 to 1973, with no increase observed after 1973; the investigation method
has not been changed in this study. In an investigation by the International
Clearinghouse

for

Birth

Defects

Monitoring

Systems*56

until

1993,

hypospadias tended to increase in Denmark and Norway, while an increase
was not indicated in the U.K., Sweden and Hungary.

The European

Registration of Congenital Anomalies has reported that in a study of 17
regions in Europe from 1980 to 1992, an increasing trend was seen in the34Strasbourg and Malta regions, while a decreasing trend was seen in Northern
Netherlands and the Glasgow and Liverpool regions.

In Australia*57,

hypospadias has tended to gradually increase from 1985, with regional
differences based on statistics for 1990 to 1992, with 21.5 per 10,000 births.
In 1997, Paulozzi et al.*58 analyzed the trend in hypospadias based onremarkably detailed data by the Metropolitan Atlanta Congenital Defects
Program and the Birth Defects Monitoring Program of the U.S., and foundthat the incidence in 1993 was about two times that in 1968, which wassignificantly higher, and that the increase rate was 2.9% a year during thisperiod, with an increase of 5.7% per year among nonwhites other than that of
1.4% per year among whites.

In particular, severe hypospadia, in which the

opening of the urethra is in the scrotum or perineal region, was reported asincreasing by 2.7 times in 1990 and by 5.5 times in 1993 compared with 1967.
In the U.S., the increase rate was high in the order: West, Central, Northeast
and Southeast regions. On the other hand, the trend in Japan is increasingslightly, according to the results of congenital anomalies monitoring by theJapan Association of Obstetricians & Gynecologists (JAOG); the incidence is 2
to slightly less than 3 per 10,000 births in recent years, which is low comparedto that of other countries.
Studies in the 1970’s showed that fetal exposure to contraceptives, pregnancy
test drugs or progesterone used for continuation of pregnancy led tohypospadias, and was related to the increase in incidence. Sharpe et al.*27
have suggested that the over twofold increase in developmental disorders ofmale reproductive organs in the past 30 to 50 years may be due to the changes
in dietary habits, increase in endogenous estrogen due to increase in body fat,increase in intake of dairy products, or the effects of estrogenic chemicals in
the environment. Goodman et al.*59 have revealed from results of experiments
on fetal rats that exposure to progesterone causes hypospadias. On the other
hand, in 1995 Raman-Wilms et al.*60 reported no relation between such
exposure and anomalies of the external genital organs. The aforementioned
report from the U.S. indicated that severe hypospadias is increasing, which
was not reported before, but the causes have not been reported; the report only
stresses the importance of study on the risk factors.
From the above literature, there are data indicating that synthetic

35

progesterone exposure is related to the incidence of hypospadias in animal
experiments, but at present there seems to be no evidence that endocrine
disruptors cause hypospadias in humans.

5.

Effects on other male reproductive organs
To briefly explain the development of male reproductive organs, at 7 weeks,
fetal sex-determining region (SRY) genes become active and produce thetestis-determining factor (TDF).

As a result, Sertoli precursor cells develop

in the primitive reproductive glands, and anti-müllerian hormone (AMH) issecreted.

Furthermore, fetal Leydig interstitial cells are induced, and thesecretion of testosterone (T) begins. During the period when the ureteral bud
develops at the base of the wolffian duct, the müllerian duct develops parallelto the wolffian duct.

In males, the müllerian duct is immediately

degenerated by AMH. By the 9th week, the external genitals consist of thegenital wall surrounding the genital tubercle, genital ridge and urogenital
sinus.

By the 12th week, the testicles descend to near the deep inguinal ring.

At around that time, the left and right genital wall and genital ridge fuse to
make the cavernous body of the urethra and scrotum, and the genital tubercle
enlarges and becomes the penis glans.

After 7 months, constriction of thetestis gubernaculum begins due to the effects of T and other androgens, and by
9 months, the testicles reach the base of the scrotum*61.
In this differentiation of the reproductive organs, testosterone (T), active type
DHT and their receptors and 5α-reductase in the androgen target cells play
an important role. If a disorder occurs in any of these processes, reproductive
organ anomalies occur.
Cryptorchidism is another abnormality that is relatively often observed alongwith hypospadias.

Cryptorchidism can be classified into four grades

according to the position of the testicles, which includes the high grade, which
remains in the abdominal cavity, and the low grade, which is at the highscrotum.

Severe hypospadias is said to often be accompanied by thecomplication of cryptorchidism. There are many theories as to the cause of
the complication; a number of factors are thought to be related.

Reportedly

son from women treated with DES from 1945 to 1971 often develop

36cryptorchidism and hypospadias, as well as decrease in reproductive functions.
According to exposure data on experimental animals and humans, highconcentrations of DES exposure cause disorders in the male reproductive
organs, including cryptorchidism, but the effects at low dose exposure havenot been clarified.

A relation between estrogen concentration in the motherand the incidence of cryptorchidism has also been indicated.

As these facts

are apparently related to the increase and decrease in reproductive organ
developmental abnormalities in the past 40 to 50 years, Sharpe et al.*27 reportthat these abnormalities may be caused by estrogen exposure during fetal
development.
Many fetal period factors are known to affect the incidence of cryptorchidism
upon birth, including bodyweight at birth, gestational age and number offetuses.

The manifestation of cryptorchidism is also reportedly influenced byseasonal changes as well as racial differences.

(The incidence of

cryptorchidism is clearly low in black males compared to white males, as is theincidence of testicular cancer.)*62
In regard to the trend in the incidence of cryptorchidism, in a study of 7,500
boys born in Oxford, England, comparison of cryptorchidism incidence
between the mid-1950’s and 1980’s showed an increase from 4.0% to 5.4% atbirth and from 0.96% to 1.86% at three months after birth*63*64.

In contrast,

according to recent research on 6,935 boys born at Mt. Sinai Hospital in New
York, the incidence of cryptorchidism was 3.7% at birth and decreased to 1.0%
at 3 months of age.

As the rate was not significantly different from thatseveral decades ago, it was concluded that there is no evidence of an increasein cryptorchidism*65.

However, this result may be due to the apparent

increase, which may have been observed because there is no standardized
diagnosis method or patient identification method, or because of regional
differences. There are no data clearly indicating an increase in cryptorchidism
in Japan, as epidemiological investigations are difficult to conduct, due toproblems with diagnosis.
In regard to abnormalities in the another external genitals, such as decreasein penis size, these can occur during any developmental stage of the
reproductive system, in the presence of factors that damage androgen actions,37

but they rarely occur alone; and their relations with endocrine disruptors are
unknown.

(3)(3) Effects on the thyroid system
Thyroid gland secretes thyroxin (T4) and triidothyronine (T3), hormones
important for both physical and mental development. Thyroid is the gland moststudied regarding the effects of endocrine disruptors next to glands. PCB anddioxin excreted into the environment accumulate in fish, and also in birds, marine
mammals and humans according to the predatory linkage. When PCBs enter the
body of animals during embryonic stage and infancy through maternal blood orbreast milk, they decrease the supply of T4 to the nervous system by binding withtransthyretin, which is the T4 transport protein in the blood*66*67*68*69. They also
cause deficiency of thyroid hormones delivered to the central nervous system bypromoting the hepato-biliary excretion of thyroid hormone into the intestines*70. In
the brain, they increase the deiodinase, which induces T3, an active thyroid
hormone from T4*70 in situ. When given to infant animals*71 they inhibit theactivity of an enzyme called chorine acetyltransferase. Animal experiments haveindicated that this action is inhibited by T4 administration but not by T3.
Regarding humans, there have been reports from the U.S. and Europe of a relation
between the consumption of fish contaminated with PCBs and the index
indicating the degree of immature nervous development in infants*72*73*74*75*76.
Regarding whether it is caused directly by actions on thyroid hormones, 105 pairof newborn babies and their mothers were studied in pairs in Netherlands. It was
found that mothers who had breast milk with high PCB concentrations had
significantly low concentrations of T4 and T3, and that blood TSH concentrations
were significantly high in the babies*74. In Japan and in Taiwan, "yusho" occurred,an accident in which PCB was mixed in edible oils. It has been reported in a study
from Taiwan that children born of "yusho" mothers have a slightly delayedcognitive capability even after seven years*77. The relation with thyroid hormone
metabolism during nervous system development has been speculated. However,there have been no reports that blood thyroid hormone levels decreasesignificantly in exposed adults or babies. There is some advocate the condition tobe similar to that of thyroid hormone refractriness*78*79, although any elusive
evidence to support this notion has not been available. There has been a report38that thyroid functions decrease as a result of professional exposure in PCB plants,
but the causes of thyroid abnormalities are autoimmune thyroid diseases, so therelation with PCBs is not known*80.

(4)(4) Others
1.

Effects on the hypothalamus and pituitary gland
There is no concrete evidence as to their effects on the hypothalamus andpituitary gland.
Effects on the immune system have been indicated particularly in TCDD and
PCB exposure. One of the receptors that mediate these effects is assumed to
be aryl hydrocarbon (Ah) receptor.
Apprehensions regarding learning disabilities and psychological disorders wereparticularly an issue in relation to PCB exposure, but there are no uniform
research results at present.

2.

Effects on wildlife
It has been reported by the United States that environmental chemicals have
had damaging effects on the reproductive functions of alligators and several
marine invertebrates in Florida. For example, a relationship was indicatedbetween a chemical spill (dicofol) into Lake Apopka in Central Florida, andshrunken penises and decreased hatching ratios for male alligators in thelake*81. Also, it was hypothesized*82 that a change in the sex ratio of herring
gulls (fewer male) in the Great Lakes resulted from estrogenic substances, suchas DDT in the environment. In Japan, imposex (i.e., male sexual characteristics
appearing in females) is reported on gastropods (IBONISHI, REISHIGAI). The
induction of imposex is known to be caused by exposure to tributyltin (TBT)
compounds, which are used as antifouling paints on ships.*83
Although several effects on wildlife have been reported, thorough researchshould be conducted to evaluate effects on humans, considering the differencesin susceptibility to endocrine disruptors between animal species.

(5)(5) Evaluation of health effects on humans
The secretion and metabolism of hormones are controlled in the body in a complex
way.

The mechanism that control the changes in the hormones is thought to be

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subject to a constant condition regulated by an adjusting mechanism, so-called“homeostasis,” including feedback control of hormone concentrations.
Therefore, as to the effects of endocrine disruptors on humans 1) many suchchemicals have little binding affinity to receptors; 2) their concentrations in theenvironment are generally low, so some doubt that they will precipitate adverse
reactions.

Excluding DES, which has strong reactivity and was administereddirectly to humans in large amounts, it is thought that, for now, necessary
measures can be taken to limit daily exposures, provided that the risks andexposure level’s of each substance can be accurately evaluated. However, for thesemeasures to succeed, the following pre-conditions must be met: 1) Physiologocal
conditions must not be such that hormone-controlled disruption could be easily
caused, including during the fetal period, 2) Unexpected synergistic effects mustnot be caused by multiple chemicals, and 3) There must be no unknown responsive
morphologies, which could not ensure dose dependability in a low-dose response.
The results of animal experiments suggest that there may be adverse effects of
endocrine disruptors on human health.

Therefore, it should be kept in mind that

although possible health effects on humans may not be excessive, the chemicals
may have some health effects.

In light of this, careful investigations andevaluations must be conducted.

In particular, as regards the effects on the fetus,

it is necessary to undertake comprehensive investigations, taking into
consideration irreversible responses whose patterns may differ from those of
adults.
Concerning those diseases whose causal relations with exposure to endocrine
disruptors appear to have been demonstrated (including endometriosis, breast
cancer, and developmental abnormalities of male reproductive organs), so far,there is no detailed information supporting such causal relations.

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