3. Physiochemical characteristics
At present, there are several sources listing suspected endocrine disruptors. Somechemicals appear in all lists, but others appear only in some lists. There are wide
variations in the selection of chemicals for these lists. This variability suggeststhat many aspects have not been clarified, such as those on whether a certain
chemical has endocrine-disrupting action, as well as the type and degree of theaction. These chemicals include the active ingredients of pesticides, industrial
chemicals, and pharmaceuticals. The production, use, or import of some of them(e.g., PCB, DDT, Chlordane) have already been prohibited in Japan. The numberof suspected endocrine disruptors may be changed, after test methods for such
substances, which are under discussion, are established and investigations haveprogressed.
The paragraphs below outline the characteristics of the major estrogenic
chemicals discussed in “A Study on the Crisis Management of Chemicals” underthe 1996 Health Sciences Research Program.
Pharmaceuticals:

Synthetic

hormones

arepharmaceuticalcompounds

administered for their possible pharmacological actions on the endocrine system.
Therefore, these hormones have endocrine disrupting actions. They include
progestogen androgen, ecdysteroid, farnesyl, and diethylstilbestrol (DES), whichcaused the so-called “DES-daughters” after it was given to pregnant women. It is
pointed out that these pharmaceuticals could be released into the environment via
human excretions. Also, certain pharmaceuticals, which are sometimes
administered to beef cattle, exert estrogenic actions. Estrogen acts as an anabolic
steroid (protein-assimilating steroid) in beef cattle.
The Joint FAO/WHO Codex Alimentarius Commission has established residue
limits for zeranol and trenbolone (i.e., synthetic hormone preparations) in beef.
Japan also has limits for these preparations. However, the Commission has noresidue limits for preparations derived from natural hormones because they occur
naturally in cattle.
Organochlorine insecticides: Organochlorine insecticides are known to be typicalendocrine disruptors which are dispersed in the environment. Among them, DDT*3
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has long been known to have estrogenic actions. These insecticides include
dichlorodiphenylethane-class pesticides (e.g., DDT and its metabolites, such as
DDD and DDE), cyclodyene-class pesticides (e.g., chlorane, oxychlordane, tnonachlor,heptachlor,heptachlor

epoxide,aldrin,anddieldrin),

hexachlorobenzene, and hexachlorocyclohexane. Many of these only slightly
decompose, and they concentrate and accumulate in the body. Therefore, theirdecay rate is known to be extremely low. Low-level and long-term exposure toorganochlorine chemicals results in their accumulation in human and animal
tissues.*4
Polychlorinated biphenyls: Polychlorinated biphenyls (PCBs) have widely been
applied over a long period for various purpose, from industrial to household,including heat-exchange mediums, adhesives, flame-resistant agents, andinsulating solutions. Their production reached several hundreds of thousands oftons in 1970.
PCBs, along with dioxin, which are chemical industrial byproducts, areproblematic because of their accumulative properties and strong toxicity. PCBsconsist of up to 209 types of homologues, most of which are remarkably stable andbiocumulative .*5 Therefore, PCB’s persistence in the environment has been ofparticular note. Most of the products on the marketplace are mixtures of various
homologues, which makes it difficult to assay environmental and biologicalsamples and to analyze the results obtained.*7The European Parliament presently defines “PCB” as a fluid containing PCBs at
0.005% or more. According to a report from the Environment Health Institute in
the UK ,*8 PCBs’ estrogenic actions were originally thought to be about one
millionth that of estradiol.*9 However, a mouse-uterus estrogen receptor-binding
test*10 determined that hydroxy bodies were compounds with estrogen activity. *11
Such bodies include 4-hydroxy-2’,4’,6’-trichlorobiphenyl, 4-hydroxy-2’,3’,4’,5’tetrachlorobiphenyl, and 4,4’-dihydroxy-2’-chlorobiphenyl, which have an activity
1/42 to 1/90 that of estradiol. S.K. Korach showed that these substances more
readily dissolve in water and are more readily excreted from the body than theirparent compounds. The endocrine-disrupting mechanisms of these substances are
known to be expressed mainly through aryl-hydrocarbon (Ah). This finding
indicates that there could be endocrine disruptors which exert their actions

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through unknown receptors. This indication is reflected in the fact that cognatetype substances of a PCB have conflicting characteristics, such as estrogenic andanti-estrogenicactions.*12Amongthe

anti-estrogenic

actions,

3,4,3’,4’-

tetrachlorobiphenyl inhibits the induction of a 52kDa protein in MCF-7 humanbreast-cancer cells.
Alkyl phenols: Alkyl phenols are microbial-degradation products of alkyl phenol
polyethoxylates (APEs) which are nonionic surfactants. APEs have been
manufactured worldwide in large amounts for various uses, including synthetic
detergents, paints, herbicides, and insecticides. The worldwide yearly productionof APEs is expected to exceed 300,000 tons for 1998.*13
These chemicals are released into the water system through the sewage system,
and are very stable. They are known to be taken into by organisms in the inland
water system and to be stored in their fatty tissues. Their basic chemical structureis alkyl phenol, which does not easily degrade. It was suggested that their residues
released in rivers can have toxic effects on aquatic life. Under such circumstances,a gradual-diminution plan is being implemented, targeted for the end of the 20thcentury.*14 The activities of p-nonyl phenol and p-oxtyl phenol, which account for
80% of the compounds with ethoxylates, can be determined in several assays,
including the proliferation activity of human breast cancer cells, such as MCF-7,gene transcription in genetically transformed chick-embryo fibroblasts, and theexpression of vitellogenin gene in rainbow trout-hepatic cells. These assays revealthat the activity of octyl phenol is slightly higher than that of nonyl phenol, but aslow as 1/1000 that of estradiol.
Phytoestrogens: Phytoestrogens from in plants differ from other chemicals in thatthey are natural compounds. These environmental substances can become
problematic, especially when livestock consume them. It has long been known thatwhen sheep consume red clover (Trifolium pratense) that contains a large amountof genistein, they develop reproductive abnormalities.*16 Phytoestrogens in plant
products, such as soy beans, are taken in by humans through foods in everyday life.
Their main active ingredients are isoflavones (genistein and daidzein) andcoumestan (coumesterol).*15 Certain kinds of fungal metabolites of cereal grains,such as zearalenone-like substances, also have estrogenic actions.*17 In addition tosubstances called exogenous estrogens, there may be other endocrine disruptors,

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such as those with androgenic actions. However, these substances have not beensystematically categorized.
Note: Bisphenol A, styrene dimers, styrene trimers, and phthalic acid esters will
be discussed in a later section (appendix).

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