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| 7th Report of Market Access Ombudsman Council (March 18, 2002) |
1. Complainant: U.S. Embassy
2. Ministry concerned: Ministry of Health, Labour and Welfare
3. Complaint:
According to the guidelines in foreign countries (the U.S. and European countries) and the OECD, "mutagenic property test" refers to testing both in vitro (relatively easy tests conducted in test tubes) and in vivo (comprehensive tests on living organisms), making a comprehensive judgement on the basis of the results of the two tests, and classifying substances in accordance with the strength of their mutagenic properties.
On the other hand, under the guidelines based on the Industrial Safety and Health Law and used by the Ministry of Health, Labour and Welfare (formerly the Ministry of Labour), the presence or absence of mutagenic properties is determined based only on the result of in vitro testing and no classification in accordance with the strength of mutagenic properties is made. Chemical substances evaluated as having mutagenic properties are specified as "handle-with-care" substances. As a results, some of the chemical substances that are found to be negative (having no mutagenic properties) in mutagenic property tests conducted in foreign countries (the United States and European countries), like glutalaldehyde, are found to be positive (having mutagenic properties) in tests conducted according to the guideline for mutagenic property tests based on the Industrial Safety and Health Law and announced as such, resulting in unfair discrimination of glutalaldehyde in the market.
Accordingly, the mutagenic property test based on the Industrial Safety and Health Law should be considered separately from screening tests and harmonized with the testing methods in foreign countries. Specifically, a system should be established to delete the chemical substances that had been found to "have mutagenic properties" in mutagenic property tests based on the Industrial Safety and Health Law from the list of chemical substances "having mutagenic properties," when reliable tests results are made available, showing that the chemical substances are found to "have no mutagenic properties" in later in-vivo tests conducted in Japan or other countries.
(Second complainant)
(1) For the following two reasons, we believe that it is necessary to establish a process to delete the substances listed as having mutagenic properties from the list when more reliable data are made available.
1) Judging from the descriptions in the "OECD Chemical Test Guidelines/ p3503, Introduction to OECD Test Guidelines for Toxicity Tests and Manual for Testing Selection and Application," it is unreasonable to uniformly use in vitro tests as a guideline for the protocol to investigate the mutagenic properties of chemical substances, as done by the Ministry of Health, Labour and Welfare. It is true that the guideline appears to support the ministry's method, saying in one section, "As described above, although the protocol for in vitro tests has been compromised due to testing composition, we can get reliable results on almost all chemical substances by using the protocol." However, in another section, the guideline says, "However, with regard to the interpretation of the results, paying attention to the effects caused by the composition of chemical substances is very important when determining the appropriateness of the protocol for testing the chemical substances in question.
2) With regard to "6. How should tests actually be utilized?," the guideline says, "However, since there are many tests that are generally used for mutagenic properties, many systems have been developed with regard to the method for testing chemical substances. They are divided into two groups for convenience's sake. That is to say, a continuous or gradual method and a pre-determined combination method. The gradual method consists of logical arrangement of tests and usually starts with two or three in vitro tests and goes on to in vitro and/or in vivo tests in the second stage. In most of the cases, which one to choose is determined by the results of the first test. The second method consists of a combination of pre-determined in vitro and in vivo tests that are to be carried out at the same time. The basic data obtained in these tests are to be investigated comprehensively. The results of mutagenic property tests should be investigated in combination with other data obtained in toxicity tests and medical dynamics studies." This passage of the guideline to the effect that tests should be carried out step by step and that results should be investigated comprehensively is consistent with our assertion made in the previous complaint. Our assertion was that "a system should be established to delete the chemical substances that had been found to "have mutagenic properties" in mutagenic property tests based on the Industrial Safety and Health Law from the list of chemical substances "having mutagenic properties," when reliable tests results are made available, showing that the chemical substances are found to "have no mutagenic properties" in later in-vivo tests conducted in Japan or any other country. Our proposal is more in line with the OECD guideline. Accordingly, we again want to ask for a review of the system.
(2) With regard to the response of the Ministry of Health, Labour and Welfare that "(the ministry) cannot change (its treatment of the chemical substances that are found to have mutagenic properties) unless they are solidly proved to have no carcinogenic properties for human being," we want to know how the ministry is treating the results of carcinogenic tests of many chemical substances conducted on many animals.
(3) What efforts are being made by the Ministry of Health, Labour and Welfare in order to enhance the reliability of the entire test results on the chemical substances listed as substances having mutagenic properties? For example, does the ministry conduct in vivo tests? Does it make efforts to obtain and study the highly reliable, useful information that is being published? With regard to substances whose evaluation has been published in various forms (in list form, etc.), doesn't the ministry take any measures at all to delete such substances from the list?
4. Corresponding Policy of the Ministries concerned:
In the current hazard-assessment testing system, two kinds of tests, one for mutagenic properties using microorganisms (in vitro) and the other for chromosomal abnormalities using mammal cell cultures (in vitro), are conducted based on Article 57-5 of the Industrial Safety and Health Law in order to screen substances for carcinogenic properties. The results of these two hazard-assessment tests determine the presence or absence of mutagenic properties. In view of the fact that many carcinogenic chemicals are found to have strong mutagenic properties in the two kinds of tests, the Ministry of Health, Labour and Welfare announces the substances found to have strong mutagenic properties in the two kinds of tests in order to protect workers from damage to their health, and guidance concerning manufacturing and handling methods is given.
The "Introduction to OECD Test Guidelines for Toxicity Tests and Manual for Testing Selection and Application" contains description supporting the combination of the two kinds of tests above as a method that can detect most of the potential mutagenic substances and carcinogenic substances having hereditary toxicity.
We cannot change our treatment of the chemical substances that are found to have mutagenic properties in the above two tests simply on the grounds of the results of in vivo tests for mutagenic properties, unless they are conclusively proved to have no carcinogenic properties for human beings.
With regard to glutalaldehyde in particular, the evaluation of its carcinogenic properties for human beings has yet to be made by the International Agency for Research on Cancer (IARC) and American Conference of Governmental Industrial Hygienists (ACGIH).
(Second corresponding policy)
(1) Tests for mutagenic properties using microorganisms (in vitro) and for chromosomal abnormalities using mammal cell cultures (in vitro) based on Article 57-5 of the Industrial Safety and Health Law are conducted in order to screen substances for carcinogenic properties. The Ministry of Health, Labour and Welfare announces the substances that have been found to have strong mutagenic properties in the two kinds of tests in order to protect workers from damage for their health, and guidance concerning manufacturing and handling methods is given.
As stated above, the system is designed to investigate as many chemical substances with carcinogenic properties as possible in order to see if administrative measures are necessary to protect workers handling the substances in question from damage to their health, by screening substances for carcinogenic properties in a simple and easy method.
The "Introduction to OECD Test Guidelines for Toxicity Tests and Manual for Testing Selection and Application" contains description supporting the combination of the two kinds of tests above as a method that can detect most of the potential mutagenic substances and carcinogenic substances that have hereditary toxicity.
As to how to use mutagenic property tests, it is described in "6. How tests should actually be utilized?" of the "Introduction to OECD Test Guidelines for Toxicity Tests and Manual for Testing Selection and Application" cited by the complainant. However, from the standpoint of investigating substances having carcinogenic properties and protecting workers from damage for their health, we cannot change our treatment of the chemical substances that are found to have mutagenic properties in the above two tests simply on the grounds of the results of in vivo tests for mutagenic properties, as they are yet to be solidly proved to have no carcinogenic properties for human being and as the evaluation of carcinogenic properties for human being has yet to be made by the International Agency for Research on Cancer (IARC) and American Conference of Governmental Industrial Hygienists (ACGIH).
(2) Since substances that are found to have carcinogenic properties in animal tests cannot be ruled out as not having carcinogenic properties for human being, we have designated such substances as those that may cause cancer or other serious damage to workers' health and announce the chemical substances in question to protect workers from damage for their health based on the opinions of experts.
(3) The Ministry of Health, Labour and Welfare has been collecting data on harmful substances through animal tests for carcinogenic properties and reproductive, developmental toxicity of the harmful substances that were reported in Japanese and foreign literature, including the substances on which the ministry has conducted tests for mutagenic properties using microorganisms and for chromosomal abnormalities using mammal cell cultures. And based on the test results and data, the ministry sets guidelines to protect workers from damage to their health.
5. Remarks
The complainant is now examining the matter.