Strategic Programs on Environmental Endocrine Disruptors '98 (SPEED '98) - Chapter I

I. The problem of Exogenous Endocrine Disrupting Chemicals

1. What are exogenous endocrine disrupting chemicals?

(1) Problems associated with exogenous endocrine disrupting chemicals

"Exogenous endocrine disrupting chemicals" are "Exogenous substances which interfere with the normal function of hormones when taken into the body." It has been pointed out recently by many researchers and experts that some chemicals in the environment may impair the reproductive processes of animals and cause malignant tumors by disrupting normal hormone function. This is an important potential problem for environmental protection.

(2) Estrogenic substances

There are several internal secretary organs (endocrine glands) that secrete a range of hormones in the human body. Among the hormones are androgen, which is secreted by the testis, estrogen (secreted by the ovary), adrenal cortex hormone, thyroid hormone, growth hormone (pituitary) and insulin (Langerhans island of the pancreas). Humans and other vertebrate animals (mammals, birds, reptiles, amphibians and fish) have much in common in terms of the kinds of their endocrine glands and the chemical composition of their hormones - steroid hormones in particular1) (See Figure 1 andTable 1).
Studies on endocrine disrupting chemicals have so far been focused on chemicals that affect the normal function of estrogen. There are several reasons for this. One is that many cases of cancer were detected in the generative organs of women who had been exposed to a synthetic estrogen (diethylstilbestrol, DES) during fetal development. This synthetic estrogen, which was first marketed in the 1930s, was widely used by women to prevent miscarriages during the 1960s and 1970s. Another reason is that many researchers have pointed out since the early 1990s that abnormal sexual behavior and reproductive organs of wildlife observed throughout the world may have been caused by DDT or other environment polluting chemicals having estrogen-like properties. In addition, in 1991 a U.S. researcher reported that nonylphenol that leaked from a test apparatus while experimenting with propagating breast cancer cells (the MCF-7 cultures) had a weak estrogen-like effect.
However, in view of various hormone-function disruption mechanisms reported by experts, chemicals having estrogen-like functions cannot explain all of these. There must be chemicals that disrupt other hormone functions. It can also be inferred that there are many mechanisms involved in the disruption of normal hormone functions.
Researchers at the U.S. Environment Protection Agency recently reported the existence of several substances that decrease androgen activity or disrupt thyroid hormone and adrenal cortex hormone functions.

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• ^* In this text, the word "exogenous" is omitted and "exogenous endocrine disrupting chemicals" are simply called "endocrine disrupting chemicals (EDCs)."
• ¹⁾ Estrogen, androgen and adrenal cortex hormones are among them

2. Hormones

(1) Roles of hormones

Hormones are secreted from the endocrine glands directly into the blood and the word "hormone" is derived from a Greek word meaning, "to stimulate." Hormones play important roles in the differentiation of the tissues of animals, their growth, the development of reproductive functions and the regulation of homeostasis. Different hormones exert effects on different organs and tissues. Hormones have different effects and power at each stage of the lifecycle of animals from development and growth to reproductive activities. Hormones are secreted from endocrine glands as they are required and travel in the bloodstream to exert their effects at target tissues or organs. Some hormones are activated and transmit signals directly or indirectly to the genetic material (DNA) in the nucleus, to induce the production of a specific protein. The hormones are then dissolved and disappear. The process of proper hormone function is complicated and it has yet to be fully elucidated at what stage of the process an endocrine disrupting chemical might interfere with the normal function of endocrine systems. (See BOX 1).

(2) How hormones work

Hormones are roughly classified into steroid hormones, amino acid-inductive hormones, and peptide (protein) hormones according to their chemical composition. They are transported in the blood in a free state or attached to carrier proteins. Once they reach their targeted tissues or organs, the hormones bind to specific receptors in the cell (in the case of steroid and amino acid-inductive hormones) or receptors on the cell surface (in the case of peptide or protein hormones), become activated, and exert effects by interacting with DNA. (See Figure 2). The concentrations of hormones in the blood are known to be very low at around the ng/ml - pg/ml level (from 1/1,000,000,000 of a gram to 1/1,000,000,000,000 of a gram per one milliliter of blood).
The activity of endocrine glands is controlled at a stable level by a feedback mechanism. For example, the hypothalamus controls hormone synthesis and secretion in the pituitary gland. When the concentration of a hormone increases to a certain level, the feedback mechanism functions and restricts the production of the hormone and thereby the activity at the receptor. This controlling function permits stable homeostasis. Hormones are said to be influenced by weather and other environmental factors, and by behavior and impulse.
When hormones are produced excessively or are insufficient in the body, diseases result. Table 1 shows a list of diseases that can be caused by an excessive or insufficient amount of hormones.

3. Mechanisms for the chemical disruption of hormone function

(1) Mechanisms of endocrine disruption

It has yet to be fully elucidated how endocrine disrupting chemicals, after entering into the body of an animal, disrupt normal hormone function or how strong their effects are compared with natural hormones. But based on research reports published in Japan and abroad to date, it can be explained as follows.
When a steroid hormone, synthesized in the endocrine gland, reaches a targeted internal organ, it binds to a receptor and causes DNA to synthesize a specific functional protein. The kind of hormone determines the kind of receptor to which it can bind, a relationship akin to that of a key and a lock.. The mechanism of endocrine disrupting chemicals has been studied from the viewpoint of a chemical substance, rather than a hormone, binding to a receptor, and this results in the gene receiving the wrong signals. When an endocrine disrupting chemical binds to a receptor, it either exerts hormone-like effects or impedes such effects. The estrogen-like effects of such chemicals as PCBs, DDT, nonylphenol and bisphenol A are examples of the former. They bind to estrogen receptors and exert estrogen-like effects. Examples of the latter are DDE (a derivative of DDT) and vinclozolin (an agricultural chemical). They bind to androgen receptors and impede androgen function (anti-androgen activity). (See Figure 3).
Recently, researchers reported the existence of chemicals that cause the production of functional protein by activating genes through effects on signal transmission routes in the cell, not by directly binding to hormone receptors. For example, dioxins do not directly bind to estrogen receptors or androgen receptors, but they do influence estrogen function indirectly by binding to a protein in the cell and activating genes.
Incidentally, medical drugs for treating endocrine diseases perform their functions by influencing hormone receptors. But some of them reinforce hormone action. For example, DES, by binding to estrogen receptors, continues sending estrogen signals to genes and this could cause cancer or lead to birth defects.

(2) Phytoestrogens

When we deal with the problems associated with endocrine disrupting chemicals, we have to pay attention to phytoestrogens. Besides man-made chemicals, there are at least 20 kinds of phytoestrogen, substances produced by plants and having estrogen-like effects. When such a substance is taken in by animals, it will influence estrogen synthesis and metabolism and may exert estrogen-like effects or anti-estrogen effects. The amount of phytoestrogen absorbed through the diet is much larger than the amount of organic chlorinated compounds that are taken in and which produce estrogen-like effects. Studies are being carried out on the absorption and metabolic mechanism of phytoestrogens in the human body, their effects on health and what combined effects they may have when they coexist with other endocrine disrupting chemicals.

4. Reports of adverse effects of endocrine disruptors on humans and wildlife

(1) Reports of adverse effects on humans and wildlife

A) Reports of adverse effects on wildlife

Adverse effects reported on fish, reptiles, birds and other wildlife include abnormal reproductive function, abnormal reproductive behavior, demasculinization and decreased hatching success. The number of these reports has increased sharply since the early 1990s. Although the cause of these effects has yet to be fully elucidated, it is strongly suspected that exposure to DDT and nonylphenol used in surface-active agents are contributing factors.
Table-2 lists the major effects of endocrine disrupting chemicals on wildlife. As seen from the table, most of the wildlife affected are aquatic animals or those living along the water's edge, but they also include some terrestrial birds.

B) Reports of adverse effects on human health

Our concern about adverse effects on human health of chemicals that disrupt estrogen functions is based on the firm medical knowledge that diethylstilbestrol (DES), which was widely used in the past, causes breast cancer or other malignant tumors. A report by a U.S. researcher in 1993 that a red-haired monkey exposed to 126pg/kg/day of dioxin developed endometriosis is noteworthy in that it traced the disruption of estrogen effects to dioxins, though similar experiments are still being conducted to confirm this result.
In 1992 it was reported that the human sperm count in Denmark had decreased over the past 50 years. A number of research groups from different countries, including Japan, have been studying the change in the sperm count in their countries. To date, no definite conclusion has been reached as to whether the number of sperm is actually decreasing.
Some studies reported that cryptorchism was observed in mice given a high dosage (0.3g / day) of phthalates, and that a decline in the number of sperm and other reproductive system disorders were observed in male-offspring from a rat exposed to bisphenol A and dioxins.
Researchers are also considering the occurrence of prostate and testis cancer and increased genital abnormalities and their possible link to endocrine disruptors. More study is needed. It was also reported that there was a sharp increase in the number of baby girls born of parents exposed to high concentrations of dioxins caused by an accident at a factory in Seveso, Italy. Researchers are studying whether or not the exposure to endocrine disrupting chemicals causes a change in the ratio of male and female babies.

C) Other areas that have to be considered

tudies on the relationship between the endocrine disrupting chemicals and their adverse effects on human beings and wildlife have been mostly focused on estrogen-like effects. But recently, reports on the study of substances impeding androgen function and those disrupting functions of other hormones such as thyroid hormones and adrenal cortex hormones were published. For example, it was reported that PCBs and dioxins disrupt the function of thyroid hormones.

(2) Uncertainties and gaps in scientific knowledge

Many scientific reports have been made on the effects of endocrine disruptors on human beings and wildlife. But the causal relationship between reported abnormalities of humans or wildlife and reported substances, and the mechanisms that cause those abnormalities have yet to be fully elucidated. It is almost certain, though, that chemical substances exist that disrupt the hormone functions of human beings and wildlife in the environment. In order to verify or otherwise the reported abnormalities, it is incumbent on us to increase the number of such reports, improve statistical analyses, study the intake of such chemicals through the polluted environment, and elucidate the mechanisms that produce the abnormalities. It is also necessary to study whether or not chemicals, including the 70-odd chemicals already pointed out, have endocrine disrupting effects and how strong their effects are. It is important for us to establish as early as possible a screening & testing method through international cooperation. (See BOX II).

Specific issues to be taken into consideration in tackling the problem of endocrine disruptors

When we study the likelihood of the effects of endocrine disrupting chemicals on humans and wildlife and their preventative measures, it is important to implement accurate environmental risk assessment by taking into account the possibility that humans and wildlife are exposed to such chemicals via pollutants in the environment, and the strength of such disruptive effects. As is clear from the description in the Basic Environment Law and the Basic Environment Plan, the prevention of adverse effects on wildlife is itself an important purpose from the standpoint of protecting the environment. From this point of view the problem should be addressed with the following points in mind.

• 1) When we wish to determine to what extent the reported effects of chemicals on wildlife can be applied to human beings, it is important to bear in mind that vertebrate animals have common hormone functions. It is also important to bear in mind that the sensitivity of wildlife to endocrine disrupting chemicals differs widely from one kind of wildlife to another.
• 2) Since reported effects on wildlife mostly concern aquatic animals or reptiles and birds living along the water's edge, it is important to pay close attention to aquatic environmental pollution in making an environment risk assessment.
• 3) It is important to keep in mind that it has yet to be fully elucidated how endocrine disrupting chemicals behave after they are discharged into the environment and that some chemicals may become endocrine disruptors after undergoing chemical transformations in the environment. It is also important to pay close attention to combined and synergistic effects in conducting environment risk assessment.
• 4) The strength of the effects of known identified endocrine disrupting chemicals is not uniform. For example, the U.S. Environmental Protection Agency reported that nonylphenol, which is said to have an estrogen-like function, is only 1/1,000,000 as strong as estrogen. It is therefore important to make further efforts to elucidate the mechanisms of hormone disrupting effects and the strength of such effects.
• 5) It is important to pay special attention to the kind of endocrine disrupting chemicals that are nonbiodegradable and are accumulated in the body through the food chain or have a slow metabolism, as very low concentrations of such substances in the body can have disruptive effects.
• 6) Chemicals that are often reported to be disruptive to estrogen activity impair the reproductive system. They have more serious effects on fetuses and infants and the effects of exposure to such chemicals during the development of fetuses are likely to appear after they grow up. It is therefore important to study environmental risk assessment and how to manage environmental risks from the standpoint of preventing delayed and long-term effects.

5. 67 chemicals suspected to be endocrine disruptors

In March 1997 the Environmental Agency set up an 'Exogenous Endocrine Disrupting Chemical Task Force' and in July the same year published an interim report describing the outcome of the review by the Task Force of scientific documents made available in Japan and abroad and indicating high priority research areas. The interim report stated that these documents have identified about 70 substances (or groups of substances) that are suspected of having endocrine disrupting effects. The number of these substances is expected to increase in the process of future study and research. It is hoped that future study and research will make it easy to identify the existence of such effects and measure the strength of disruptive effects.
The use of such substances and the legal restrictions on them are described here. It has to be noted that the restrictions and environmental monitoring were not implemented from the standpoint of coping with endocrine disrupting effects. It is therefore necessary to review the present restrictions and monitoring activities, while enhancing our scientific knowledge.

(1) Environmental laws and regulations concerning potential endocrine disruptors

The 67 substances have diverse chemical compositions and they are produced and used in various ways. More than 40 of them are active principles of agricultural chemicals. The production and use of DDT, 2,4,5-T, aldrin, dieldrin, endrin, chlordane and some other persistent agricultural chemicals have been suspended since the 1970s. Several other chemicals such as toxaphene and mirex have never been used in Japan.
Meanwhile, DDT, HCB and chlordane are designated as first-class special chemical substances under the 'Chemical Substances Control Law' and the production, use and import of such substances are basically prohibited except for special cases such as for testing and research. The use of organic tin compounds such as TPT and TBT as antifouling paints on ships has decreased drastically after they were designated as first- or second-class special chemical substances under the same law in 1990.
As to dioxins and furans, incinerators and other major sources of pollution are restricted under the 'Air Pollution Control Law' and the 'Waste Disposal Law.'
The production of bisphenol A, a component of plastics, some of the phthalic-acid esters (used as plasticizers), and nonylphenol-ethoxylate (which produces nonylphenol by decomposition), a surface-active agent, are currently between scores of thousands and several hundreds of thousand tons a year. The Food Hygiene Law limits the level of bisphenol A that can leak from food containers.
The heavy metals cadmium, lead and mercury, which are suspected of having endocrine disrupting properties, are subject to restrictions under the 'Water Pollution Control Law' and the 'Waste Disposal Law.' Cadmium and lead are also subject to restrictions under the 'Air Pollution Control Law.'
Table-3 shows restrictions on these substances and how they are used.

(2) Monitoring of environmental pollution by potential endocrine disruptors

The Environmental Agency has been conducting an 'Environmental Survey and Wildlife Monitoring of Chemicals' since 1974 and publishes annually the outcome of the investigation. This investigation is designed to monitor the level of pollution on the general environment (air, water quality, sediment quality, wildlife, etc.) by chemicals. The investigations have been conducted on high-priority harmful substances. Besides these investigations, the Agency and local governments have been conducting various monitoring surveys of the environment. The Agency and local governments have monitored annually or in specified years 47 of the chemicals suspected of being endocrine disrupting chemicals and 24 of them have been detected. The results of the monitoring are described in an interim report published in July 1997. The report states, for example, that the concentration of PCB in the bodies of animals remains almost unchanged 20 years after the use of the chemical was suspended. DDT was not detected in water but its concentration in sediments was reported to have remained unchanged. Five of the phthalic-acid esters, which are considered to have endocrine disrupting properties, were detected in water and sediment.
As for octylphenol, nonylphenol, bisphenol A, and dimeric and trimeric styrenes, whose burden on the environment is considerable, and some substances that were not covered in past investigations, the method of measurement will be improved and data will be accumulated.
Meanwhile, the Environment Agency is not in possession of enough information concerning the production and use of endocrine disrupting chemicals, the routes of their discharge to the environment and the quantity discharged, except for some substances under restriction. The Agency, therefore, intends to strive to collect information on environment loads of these chemicals.

6. International approaches to the problem

In July 1991, Dr. Theo Colborn et al. issued a "Wingspread" statement on environmental hormone problems, calling for the promotion of study in this area. International awareness of the problem was raised when they published 'Our Stolen Future' in 1996. In May 1997, the environmental ministers of eight countries met in Miami, U.S., to discuss Children's Environmental Health and they specifically addressed the problem of endocrine disrupting chemicals and issued a declaration. It stated that 'infants and children may be at particular risk to the potential effects of these contaminants. Children may be exposed to endocrine disrupting chemicals in utero, through breast milk and in the environment' and it stressed the importance of continuing efforts to develop an international assessment of the state of the science, identify and prioritize research needs and gaps in data. It also called for the development of cooperatively-based risk management or pollution prevention strategies as major sources and environmental fates of endocrine disrupting chemicals are identified, and stressed the need to continue to inform the public as knowledge is gained.
According to a report compiled by the OECD in November 1997, no countries had specific restrictions on the discharge of endocrine disrupting chemicals. Because of the effects of such chemicals, however, some countries, including the United States and the U.K., have begun to tackle the problem. In March this year, the OECD formed a working group of experts with the aim of establishing an internationally harmonized guideline on screening tests for endocrine disrupting chemicals.

(1)Approaches in other countries

A) United States of America

In the United States, the Food Quality Protection Act (FQPA) and the Safe Drinking Water Act (SDWA) Amendments were enacted in August 1996, mandating the Environmental Protection Agency to prepare a screening program for chemicals having estrogenic or other endocrine disrupting properties within two years and implement the program within three years. The Agency is expected to come up with a draft program in August this year. The National Academy of Sciences is now preparing a report on endocrine disrupting chemical problems for release by the end of this year.

B) United Kingdom

In January this year, the Environment Agency, an independent agency of the Department of the Environment, Transport and the Regions, presented priority study projects and called on industry to restrict the discharge of endocrine disrupting chemicals and to introduce safer substitutes. The agency has been asking for public comments on the matter. The deadline for submitting comments was set at the end of April 1998. The Agency is expected to consider administrative measures on the basis of public comments. The Department is also preparing a priority list and promoting research and study on effects on the marine environment.

(2) The approach of international organizations

A) The Organization for Economic Cooperation and Development (OECD)

The OEDC decided in November 1996 to develop test guidelines, including screening methods, for endocrine disrupting chemicals.
The first meeting of the working group was held in March 1998 to start activities with a view to developing a harmonized testing strategy for endocrine disruptors. A total of 45 experts from 19 countries and regions attended the meeting and they decided on a framework for their future activities. Japan sent four experts to the meeting.

B) The Intergovernmental Forum on Chemical Safety (IFCS)

The problem of endocrine disrupting chemicals was discussed at the IFCS held in Ottawa, Canada, in February 1997 and the participants confirmed the importance of the problem. Because of a lack of scientific studies, they advised the Inter-Organization Programme for the Sound Management of Chemicals (IOMC) to influence organizations concerned to promote the study and international exchange of information.
Based on the IFCS recommendation, a steering group of the International Programme on Chemical Safety (IPCS) and the OECD was established and it met for the first time in March 1998 to establish an inventory of research activities on endocrine disruptors. The meeting agreed to provide an international report by the spring of 2000.

C) Start of international talks to adopt a legally binding instrument for the restriction of persistent organic pollutants

In the 'Global Programme on Action for the Protection of the Marine Environment from Land-based Activities' adopted in November 1995, it was agreed to adopt a legally binding instrument to restrict 12 persistent organic pollutants. All 12 pollutants are suspected to be endocrine disrupting chemicals.
International meetings to work out and adopt a legally binding instrument will start in June this year under the leadership of the United Nations Environment Program (UNEP). The documents are expected to form an important framework to deal with the problem not only for industrialized countries but also in a global context.

D) Others

The 'Convention on the Prior Informed Consent Procedure for Certain Hazardous Chemicals and Pesticides in International Trade' is now being negotiated under the leadership of UNEP. It will require a country exporting harmful chemicals and pesticides to obtain prior consent from the importing country in order to manage international trade of harmful chemicals in an environmentally sound manner. Endocrine disrupting chemicals are now included among the substances requiring prior informed consent. An early adoption of the convention, therefore, is important in promoting international efforts against this problem.