3. Measures to protect human health
Large quantities of chemicals are used in Japan. The number of these chemicals is
estimated at several tens of thousands. Time, budget, and work force available totake urgent measures to protect human health against a number of chemicals arevery limited. Therefore, it is necessary to set up a specific program under which
studies and evaluations are efficiently carried out.
In these studies, the target chemicals should be divided into two categories, based
on toxicity information: a) chemicals suspected to exert endocrine disrupting
activities and b) chemicals with insufficient information to decide whether they
are endocrine disruptors. Priority should given to the former chemicals (see (1)below). The latter chemicals should be screened using a high-throughput
screening method (robot automated technology) (see (2) below).
Below is a specific program for studies and evaluations. On the basis of existingdata on toxicity and screening, chemicals should be prioritized for detailed
investigations.
(1) Research on chemicals suspected to be endocrine disruptors
Health effects of chemicals on humans are determined on the basis of the extent of
the toxicity of these chemicals and their exposure level. Japan will conduct thefollowing activities to assess the risk of each of the chemicals suspected to haveendocrine-disrupting effects.
1.

Gathering information
Japan will gather background information showing that the chemicals are
suspected to have endocrine-disrupting actions, together with information on
their physiochemical characteristics necessary to conduct the studies andresearch given in sections 2) through 5).

2.

Investigating exposure pathways
Japan will identify exposure levels and pathways for each chemical included
in foods, apparatus and containers for food use, toys, household-use articles,
drinking water, and air. We will determine exposure levels and also51

investigate dynamics of the chemical in the environment.
3.

Studying metabolism
Japan will consider the toxicity of metabolites as well as the toxicity of theoriginal chemicals because chemicals may be metabolized and change into
various metabolites in the human body. We will identify the distribution ofchemicals in the human body, and will clarify mechanisms of endocrinedisrupting activities.

4.

Studying multiple-generation reproduction
Japan will conduct two-generation reproduction studies based on information
and research, and study results obtained in 1) and 3), to provide valuable
information for the risk assessment of chemicals. If necessary, we will conduct
a 28-day repeated-dose toxicity study, utero-trophic assay, and Hershberger
assay before the performance of the multiple-generation reproductive study.
The two-generation study is globally considered to be most appropriate forinvestigating health effects of endocrine disruptors, including those on thefetus. This study observes the effects on adult animals and their twogeneration offspring, by administrating chemicals to the animals who areallowed to reproduce.

5.

Conducting risk assessments
Japan will conduct risk assessments based on information and results ofresearch obtained under 1) through 4) above.

(2) Other methods of checking chemicals
The chemicals used in Japan are estimated at several tens of thousands. There is
the possibility that these chemicals may exert endocrine disrupting activities inhumans and wildlife, now or in the future. Therefore, it is necessary to examine
chemicals without sufficient observations to see whether there is the possibility.
Examinations should be conducted using test systems devised for exclusively that
purpose (Plural test systems using animals are considered to be necessary).
However, these tests are very time-consuming and costly. It is almost impossible totest all target chemicals simultaneously. Therefore, for efficiency and economy,priority should be set based on certain indications. There is a common idea among52

developed countries: it is necessary to develop the framework of such an approachin international harmonization, given that a great number of chemicals are
distributed worldwide. Currently, Japan, the United States and European
countries are working together to promote examinations through organizations
such as the WHO and the OECD.
1.

High throughput pre-screening (HTPS)
The high throughput pre-screening system uses robotic technology to obtain
information on bioactivity for several chemicals in a short time, by conducting
comparably simple tests. The information obtained is used for setting
priorities for target chemicals for the next-tier study systems. In practice, thedevice operates a reaction system using cultured-cell strains integrated with ahormone receptor and its response gene, and detects the presence or absenceof actions of estrogens, androgens, and thyroid hormones on each receptor, as
gene-transcription activity.

2.

Priority setting
Priorities should be set so that substances exhibiting overt or almost overt
health risks are selected for next-stage study systems, based on conventional
epidemiological and experimental studies. However, few substances exhibit
overt health risks. Most of the substances lack useful data on their biologicaleffects. Therefore, priorities should be set, based on results of HTPS.

3.

Conduct of studiesa) Screening
Screening is designed to provide necessary data to sort out those substances
which may have endocrine disrupting actions. If needed, based on HTPS
results, further studies should be conducted, including 28-day repeated dose
toxicity studies, utero-trophic assays, and Hershberger assays.
b) Detailed tests
Detailed tests identify whether substances are endocrine disruptors andcharacterize the endocrine-disrupting actions of these substances in humans,
including a dose-response relationship. The tests not only identify thesesubstances, but also determine whether their activities are direct or indirect.
In addition, they yield data useful for conducting risk assessments on humans.

53

Additional tests may be required for definitive risk assessments.
4.

Risk assessments
Risk assessments are conducted, based on results obtained under 1) through3)

5.

Considerations
The tests mentioned in section (2) have a little accumulation of data on thereliability of test methods, because these problems are quite new. It isnecessary to validate test methods used in each stage of screening and specificstudies, such as multi-generation reproduction studies. Also, international
coordination should be promoted for the effective and appropriate
performance of studies.

(3)

Other research

The following research should be performed, in addition to the studies given in
sections (1) and (2).
1.

Exposurea) Development of elution tests and/or material tests for foods, foodpackages/containers, and toys
It is necessary to develop elution tests and material tests for food containers
and toys, and residue tests (in foods) for some chemicals suspected of being
endocrine disruptors. Because elution volumes vary with solvent, temperature,and time, these evaluation methods should be suited to the actual chemical
intake of humans. The methods should be simple and internationallystandardized. Also, it will be important to develop standard assays for thesechemicals in human blood and abdominal fluid.
b) Investigation of exposure from foods, food packages/containers, and toys
Because there are a wide variety of foods, food containers, and toys, it isessential to investigate exposure to chemicals from these pathways. It is also
necessary to investigate such exposures comprehensively, along with thosefrom drinking water and the atmosphere. Then, these results and toxicity
study results should be compared. If needed, measures should be taken to54

reduce exposure to these individual chemicals. Reports indicate that someendocrine disruptors accumulate in the human body, which can affect health.
It is vital to determine the levels of chemicals taken into the body by analyzing
biological samples (blood, abdominal fluid, human milk) when conducting risk
assessments. In particular, test results from umbilical cord blood areimportant to understand fetal exposure, and results from human milk tounderstand infant exposures. In addition, these samples should be preserved
for a long period for future studies.
2.

Toxicity studies
There are problems to solve on toxicity study methods and the interpretationof the study results. These problems include the three given below.
Assessment parameters in individual study methods should be set from acomprehensive aspect. Therefore, it is necessary to encourage research of
setting these parameters.
a) Studies on individual chemicals
Inverted U effects (Clarification of action mechanisms)
There are reports that certain types of chemicals exhibit the so-called inverted
U effect in animal experiments and in-vitro tests.*87 This effect refers tochemicals which exhibit a positive dose-relationship at a high dose but anegative dose-relationship at a low dose, so that the nature of the response
differs for low- and high-doses. The reliability of such reports is still open toquestion, because these reports are limited to in-vivo results, for which
reproducibility can not always be confirmed. Conventional toxicity studies andevaluations have been based on the dose-relationship, assuming that there
is a threshold. So far, the inverted U effect has not been examined. Therefore,
it is necessary to confirm whether the inverted U effect exists. If its existence
is confirmed, action mechanisms should be immediately identified.
Fetal and neonatal exposures
There are reports that offspring from animals fed certain types of chemicals
during pregnancy had malformations, and some of the offspring developed
learning disorders, cancers, immunological hypofunctions, and reproductive
disorders, after reaching adulthood. Mechanisms should be clarified in a
multi-faceted and comprehensive approach because the mechanisms of the55

development of these effects are not clear, and it can take a long time for theeffects to be expressed.
Quantitative studies for structure-activity relationshipResearch into structure-activity relationships is aimed at identifying thecharacteristics of a chemical by mathematically analyzing the chemical
structure using a computer. This type of research is widely used for selecting
chemicals in developing new pharmaceuticals because it has a number of
merits, including

savings in cost, time, and experimental animals when

conducting risk assessments. On the other hand, such research shows
reliability and usefulness only for some types of chemicals because 1) it cannot
be used for chemicals like steroid hormones, in which a slight change in a side
chain causes great changes in bioactivity, and 2) there is limited information
on human health-effects. However, if a comprehensive quantitative study forstructure-activity relationships were to be conducted, it could become aneffective approach for easily evaluating toxicity effects on humans. Such a
study would be based on screening test data to be obtained from the researchand studies given in (1) above, and detailed study data including chronic
toxicity studies, as well as those on the physiochemical properties of existingchemicals.
b) Combined effects of multiple endocrine disruptors
There are reports that separate chemicals did not have any effect on
experimental animals in some studies, but multiple chemicals, whencombined, did have an effect. In addition to the effects of separate chemicals,
there is an emerging concern about combined effects of chemicals to whichhumans are or may be exposed at rather high levels. John McLachlan (whotook an important role in the argument for combined effects) and others hadreported that multiple chemicals, when combined, exhibited about 1,000 times
higher synergistic effects. They withdrew the report due to lack of
reproducibility.*89 At the moment, the additive effects of endocrine disruptors
are indicated but synergistic effects are not confirmed. However, the potential
synergistic effects of multiple chemicals may not be ruled out. Therefore,
additional studies are needed on such potentiality.
c) Phytoestrogens
Phytoestrogens are consumed through foods in larger amounts than are

56

synthetic chemicals. These estrogens are reported to have higher estrogenic
activity than that of some synthetic chemicals in in-vitro tests *90 and may have
health effects on humans. However, there is the interesting fact that although
Japanese people consume a large amount of soybeans, which include
phytoestrogens such as genistein, the incidence of breast cancer is lower inJapanese women than in Western women. Humans have a long history of
consuming phytoestrogens. There is an assumption that humans havedeveloped resistance to them through a feedback action and a metabolizing
or eliminating action for certain types of estrogen-like substances. It isnecessary to clarify the actions of phytoestrgens the living body, including
those between species.
3.

Epidemiological studies
It is a fact that endocrine disruptors occur in the environment and have someeffects on people. Also, some populations are anticipated to be occupationally
exposed to high levels of endocrine disruptors. Therefore, it is necessary to
identify how Japanese people’s health can be affected by occupational
exposure to endocrine disruptors according to exposure level. To that end,
effective research should be conducted on human health effects based on
carefully designed epidemiological research.
The effects to be investigated include those on male and female genital organs
and reproductive functions, the hormonally mediated cancers, and thehormonal environment of the body. Exposure levels should be exactly
determined from biological samples, and factors which may signify arelationship between exposure to endocrine disruptors and health effects
should be investigated, including phytoestrogens and endogenous hormones.
Epidemiological studies should be conducted on the general public and on
occupational populations, using suitable methods including case-control
studies, cohort studies, cross-sectional studies, ecological studies (regionalrelationship studies), and random comparative tests. Also, attention should be
paid to sampling methods, the number of required subjects, setting of controls,and ethical aspects of the studies.

(4) Development of implementation systems for research57

Research required to solve endocrine disruptor problems cover a wide variety ofareas. For the smooth conduct of research, a framework should be established.
1.

Structuring of a new framework
Since 1996, the Ministry of Health and Welfare has supported research andstudies on endocrine-disruptor problems in a program of “Health Sciences
Research” with a view to preventing health hazards. This program has been
carried out in cooperation with the industrial and academic sectors. To further
promot research, the Ministry needs to strengthen its planning and evaluation
systems for research. The Ministry also needs to promote comprehensive
research, including voluntary research by industry and the publication of databy other countries and related governmental agencies.

2.

Training and securing researchers
Japan has fewer researchers capable of evaluating chemical safety than doother countries. Researchers are required to acquire a wide range of expertisebeyond conventional academic boundaries. Japan needs to develop a training
system to secure researchers capable of solving chemical-safety problems.

3.

Procurement of instruments for researchHighly sensitive instruments are required to study endocrine disruptors
because these chemicals are considered to have health effects on humans attrace levels. Japan needs to install state-of-the-art analytical instruments in
our laboratories.

4.

Efficient performance of research
The number of chemicals distributed in the world is estimated at the tens of
thousands. Cost-saving approaches are needed to evaluate the safety of thesechemicals. Japan has to promote research under a practical program with along-term view to protect human health (e.g., the tiered program adopted in
the United States). Such research must be performed efficiently incollaboration with the private, academic, and industrial sectors.

( 5 ) Development of an information management and distribution system, basedon a database
Currently, various types of research and studies are, and will be, conducted on58

endocrine disruptors by the Ministry of Health and Welfare and the other agencies
concerned, several industries, and non-governmental organizations, from theirown particular view points. This will result in the generation of great amounts of
information. Such information should be compiled into a database in order toutilize it effectively for several purposes such as regulation, research, andpublication. The Ministry of Health and Welfare is scheduled to build up a
database on endocrine disruptors because it already has a database on humanhealth.
(6) Encouragement of international cooperation
Japan needs to work together with major international organizations and foreigncountries which handle problems of endocrine disruptors. It should also take aleading part in international cooperation. The following are the activities Japan
will carry out:
1.

The International Programme on Chemical Safety / The World HealthOrganization (IPCS/WHO)l

To participate in the risk assessment of endocrine disruptors, results of which
will be compiled in two years by the IPCS/WHO.

l

To compile and assess results of various studies conducted in Japan, and tocontribute to international risk assessments.

l

To coordinate databases between the IPCS/WHO and Japan, in order toenable them to be mutually accessible.

l

To provide information on the experience obtained in building up a databasein Japan.

2.

The Organization of Economic Cooperation and Development (OECD)l

To help to set up an assessment system for endocrine disruptors, based on
study results obtained in Japan. The establishment of this system is under
way in the OECD.

l

To participate in the program for drawing up test guidelines for endocrine
disruptors.
In practice, Japan will help to draft revised versions of the 28-day repeatedtoxicity study, utero-trophic assay, Hershberger assay, and multi-generation
reproduction study. These study methods should be reviewed, from the focus

59

on the assessment of Endocrine disruptors.
l

To conduct studies under the revised guidelines.

3.

The United Statesl

To exchange validation results of assessment systems and compare results
between Japan and the United States.

l

To coordinate target items for research between our countries to improve theaccuracy of tests, heighten efficiency, and reduce costs.

The United States is validating an assessment system for endocrine disruptors
and compiling the results. The assessment system consists mainly of three tiers:
high throughput pre-screening, screening, and detailed testing. This system issimilar to that used in Japan.

60