- Email: [email protected]
O XIX A.7 Regulatory issues in the aftermath of international harmonization of mutagenicity test guidelines
SI92
S·XIX : Regulation update and industrial views
10 XIX A.sl
New OECD genotoxlelly guIdelines: A crill cal review In relation to other International guIdelines
David Kirkland. Cooance Laboratories Europe, OtleyRoad. Harrogate. HG3 JPY, UK The production of new and revised GECD genotoxicity guidelines has taken nearly 6 years to complete. During the same period a significant initiative to harmonise the guidelines relating to pharmaceutical registration (International Conference on Harmonisation, ICH) has also been operating, and has produced guidelines on genotoxicity tests. Great efforts have been made to clarify the ambiguities of earlier guidelines, and to harmon ise across various national and regional guidelines that have been published since the first DECO genotoxicity documents of 1983. Significant agreements have been reached in many areas of In vitro and m vivo testing, eg • acceptable solvents and when untreated controls are needed • upper limits for testing in terms of concentration and toxicity • when In vivo testing can be reduced to a single sex or a single dose level • criteria for positive controls and positive responses However, there are still some important differences in detail and emphasis between ICH and OECD guidelines, eg • conditions under which precipitates are tested in mammalian cells in vitro • whether an Ames test is unnecessary for bactericidal substances • the use of long term (24 hr) treatments in the mouse lymphoma assay • what is meant by "confirmation" of negative results in vitro, how and where it can be achieved These will need to be resolved. Keyword(s): genotoxicity testing; guidelines; harmonisation
10 XIX A.61
Interpretation of regulalory guIdelines: AD Industrial vIew
Leigh Henderson. ENJlronmentai Safety Laboratory, Unileoer Research, Colworth House, Shambrook; Bedfordshire, UK In the last few years considerable internat ional efforts have been made to update and harmonize genotoxicology guidelines. The culrrunanon of these efforts has been the product ion of the International Conference on Harmonization (lCH) STEP documents and the revised OECD guidelines. Ideally. guidelines should be flexible enough to allow the customizing of the test system to maximize the chance of detecting a genotoxic substance. taking into account the nature of the test substance. However they should be sufficiently prescriptive so that industrial sponsors can design a protocol and have no doubt that this WIllbe accepted by the regulatory authority to which It is submitted. Specific requirements of the new GECD guidelines which may give rise to different interpretations will be discussed in this presentation. Deficiencies in data to support individual protocol requirements will also be discussed. Keyword(s): Genotoxicology guidelines; OECD
10 XIX A.7J
Regulatory Issues In the anermath of International harmonIzation of mutagenlclty test guidelines
David H. Blakey. MUlagenesis Section, Environmental Health Directorate, HeallhCanada. Enuironmental Health Centre. PL 0803.4, Tunney5 Pasture; Onawa; Ontario KIA OU. Canada At the last International Conference on Environmental Mutagens in 1993, a satellite workshop was held in Melbourne on international harmonization of test guidelines . At that workshop, experts from many countries reached a common understand ing of the characteristics of mutagenicity assays commonly used for regulatory purposes, while establishing the minimum criteria required to produce reliable results. The success of the melbourne workshop and other. similar exercises, led to the generation of new. updated OECD test guidelines. In the revised OECD guidelines. a balance was sough between the
need for adequate test data and the cost of such testing. While many believe that this balance was achieved, there is still debate over several basic issues of testing and mterpretanon, For example, the requirement for repeat tests, and duplicate plates has been challenged . Other important issues include the need for reliable methods to demonstrate bone marrow exposure in a negative micronucleus assay and the best way to measure aneuploidy. Technological advances are occurring rapidly in genetic toxicology. The process that leads to the acceptance of new assays by the GECD and other agencies must keep pace with this increasing rate of method development. Ultimately, this process must allow the timely evolution of testing strategies to encorporate the benefits offered by reliable new assays, while avoiding the acceptance of unproven technologies and assays that offer no advantage over existing methods. Keyword(s): GECD; guidelines; issue
10 XIX A.sl
Unresolved problems In guldellnes for mutagenesis
Daniel Marzin.llIStitul Pasteur de Lille, Laboratory a/Toxicology, J. rue du Pr Calmette B.P.US - S9019UUE Cedex, France Many authorities proposed a battery of tests or a strategy to evaluate the mutagenic potential of chemicals or material used for human applications but some particular cases are not taken into account. In the case of medical applications, biomaterials should be tested but in VIlIO tests are not adapted and the battery is limited to in vitro assays using extracts of the biomaterial. But the methods developped to obtain extracts are poorly validated to test mutagenic activities and some data demonstrated that the conditions of extraction can influence the mutagenic response. Biotechnological products used as drugs are submitted to mutagenic ity testing prinCIpally to evaluate the risk of mutagenic impurities but some cases of false positive results were demonstrated for example in the Ames test and the interference of polypeptides in the mutagenic potential of such impurities was not clearly cstablished. In the field of pesticides, some microorganisms used as biopesticides could contain mutagenic endotoxin or exotoxin and such preparations should be tested for mutagenic porenual and methologies should be adapted to avoid to rmss a microorganism than could growth and spread mutagens in the environment. These few examples demonstrate that some cases are not strictly covered by regulatories, an adaptation of the methodologies is necessary on a case by case bases to avoid pitfalls of false positive or of false negative results.
POSTERS A
Ip Xlx.ttl
Revising the UKEMS statistics guldellnes for the new millennium
David P. Lovell' . Michael Rt. Green 2 . I BIBRA Intemationai, Woodmansteme Road, Carshalton, Surrey, UK; 1 MRC CellMutation Unit, Sussex University, Falmet: Brighton. UK In 1989 UKEMS pubhshed Its 'Guidelines for the Statistical Analysis of Mutagenicity Data' (Cambridge University Press). The format of that initiative involved a unique collaboration, with a series of joint working parties of genetic toxicologists and statisticians. UKEMS has decided that it is time to look again at statistics in genetic toxicology. to see whether the approaches suggested in 1989 have been successful and to ask whether revised or novel statistical approaches may be appropriate. They wish to extend the inillative to EEMS members to participate in order to provide a wider European dimension to the discussion. As a starting point short articles have been submitted to UKEMS and EEMS newsletter, and to statisticians through the UK Statisticians in the Pharmaceutical Industry (PSI) . To stimulate discussion a number of crucial issues were highlighted : Does the assessment of historical control data have a role in the interpretation of data? Are there ways of incorporating this into a formal analysis? Is it more important to try to identify positive VCI'SWI negative results or to quant ify the size of effects? What is an appropriate level of replication within an assay ?
S·XIX : Regulation update and industrial views
10 XIX A.sl
New OECD genotoxlelly guIdelines: A crill cal review In relation to other International guIdelines
David Kirkland. Cooance Laboratories Europe, OtleyRoad. Harrogate. HG3 JPY, UK The production of new and revised GECD genotoxicity guidelines has taken nearly 6 years to complete. During the same period a significant initiative to harmonise the guidelines relating to pharmaceutical registration (International Conference on Harmonisation, ICH) has also been operating, and has produced guidelines on genotoxicity tests. Great efforts have been made to clarify the ambiguities of earlier guidelines, and to harmon ise across various national and regional guidelines that have been published since the first DECO genotoxicity documents of 1983. Significant agreements have been reached in many areas of In vitro and m vivo testing, eg • acceptable solvents and when untreated controls are needed • upper limits for testing in terms of concentration and toxicity • when In vivo testing can be reduced to a single sex or a single dose level • criteria for positive controls and positive responses However, there are still some important differences in detail and emphasis between ICH and OECD guidelines, eg • conditions under which precipitates are tested in mammalian cells in vitro • whether an Ames test is unnecessary for bactericidal substances • the use of long term (24 hr) treatments in the mouse lymphoma assay • what is meant by "confirmation" of negative results in vitro, how and where it can be achieved These will need to be resolved. Keyword(s): genotoxicity testing; guidelines; harmonisation
10 XIX A.61
Interpretation of regulalory guIdelines: AD Industrial vIew
Leigh Henderson. ENJlronmentai Safety Laboratory, Unileoer Research, Colworth House, Shambrook; Bedfordshire, UK In the last few years considerable internat ional efforts have been made to update and harmonize genotoxicology guidelines. The culrrunanon of these efforts has been the product ion of the International Conference on Harmonization (lCH) STEP documents and the revised OECD guidelines. Ideally. guidelines should be flexible enough to allow the customizing of the test system to maximize the chance of detecting a genotoxic substance. taking into account the nature of the test substance. However they should be sufficiently prescriptive so that industrial sponsors can design a protocol and have no doubt that this WIllbe accepted by the regulatory authority to which It is submitted. Specific requirements of the new GECD guidelines which may give rise to different interpretations will be discussed in this presentation. Deficiencies in data to support individual protocol requirements will also be discussed. Keyword(s): Genotoxicology guidelines; OECD
10 XIX A.7J
Regulatory Issues In the anermath of International harmonIzation of mutagenlclty test guidelines
David H. Blakey. MUlagenesis Section, Environmental Health Directorate, HeallhCanada. Enuironmental Health Centre. PL 0803.4, Tunney5 Pasture; Onawa; Ontario KIA OU. Canada At the last International Conference on Environmental Mutagens in 1993, a satellite workshop was held in Melbourne on international harmonization of test guidelines . At that workshop, experts from many countries reached a common understand ing of the characteristics of mutagenicity assays commonly used for regulatory purposes, while establishing the minimum criteria required to produce reliable results. The success of the melbourne workshop and other. similar exercises, led to the generation of new. updated OECD test guidelines. In the revised OECD guidelines. a balance was sough between the
need for adequate test data and the cost of such testing. While many believe that this balance was achieved, there is still debate over several basic issues of testing and mterpretanon, For example, the requirement for repeat tests, and duplicate plates has been challenged . Other important issues include the need for reliable methods to demonstrate bone marrow exposure in a negative micronucleus assay and the best way to measure aneuploidy. Technological advances are occurring rapidly in genetic toxicology. The process that leads to the acceptance of new assays by the GECD and other agencies must keep pace with this increasing rate of method development. Ultimately, this process must allow the timely evolution of testing strategies to encorporate the benefits offered by reliable new assays, while avoiding the acceptance of unproven technologies and assays that offer no advantage over existing methods. Keyword(s): GECD; guidelines; issue
10 XIX A.sl
Unresolved problems In guldellnes for mutagenesis
Daniel Marzin.llIStitul Pasteur de Lille, Laboratory a/Toxicology, J. rue du Pr Calmette B.P.US - S9019UUE Cedex, France Many authorities proposed a battery of tests or a strategy to evaluate the mutagenic potential of chemicals or material used for human applications but some particular cases are not taken into account. In the case of medical applications, biomaterials should be tested but in VIlIO tests are not adapted and the battery is limited to in vitro assays using extracts of the biomaterial. But the methods developped to obtain extracts are poorly validated to test mutagenic activities and some data demonstrated that the conditions of extraction can influence the mutagenic response. Biotechnological products used as drugs are submitted to mutagenic ity testing prinCIpally to evaluate the risk of mutagenic impurities but some cases of false positive results were demonstrated for example in the Ames test and the interference of polypeptides in the mutagenic potential of such impurities was not clearly cstablished. In the field of pesticides, some microorganisms used as biopesticides could contain mutagenic endotoxin or exotoxin and such preparations should be tested for mutagenic porenual and methologies should be adapted to avoid to rmss a microorganism than could growth and spread mutagens in the environment. These few examples demonstrate that some cases are not strictly covered by regulatories, an adaptation of the methodologies is necessary on a case by case bases to avoid pitfalls of false positive or of false negative results.
POSTERS A
Ip Xlx.ttl
Revising the UKEMS statistics guldellnes for the new millennium
David P. Lovell' . Michael Rt. Green 2 . I BIBRA Intemationai, Woodmansteme Road, Carshalton, Surrey, UK; 1 MRC CellMutation Unit, Sussex University, Falmet: Brighton. UK In 1989 UKEMS pubhshed Its 'Guidelines for the Statistical Analysis of Mutagenicity Data' (Cambridge University Press). The format of that initiative involved a unique collaboration, with a series of joint working parties of genetic toxicologists and statisticians. UKEMS has decided that it is time to look again at statistics in genetic toxicology. to see whether the approaches suggested in 1989 have been successful and to ask whether revised or novel statistical approaches may be appropriate. They wish to extend the inillative to EEMS members to participate in order to provide a wider European dimension to the discussion. As a starting point short articles have been submitted to UKEMS and EEMS newsletter, and to statisticians through the UK Statisticians in the Pharmaceutical Industry (PSI) . To stimulate discussion a number of crucial issues were highlighted : Does the assessment of historical control data have a role in the interpretation of data? Are there ways of incorporating this into a formal analysis? Is it more important to try to identify positive VCI'SWI negative results or to quant ify the size of effects? What is an appropriate level of replication within an assay ?