The effect of REACH implementation on genotoxicity and carcinogenicity testing Jan van Benthem

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1 The effect of REACH implementation on genotoxicity and carcinogenicity testing Jan van Benthem National Institute for Public Health and the Environment Laboratory for Health Protection Research Bilthoven The Netherlands Facts: This talk is my personal view and may deviate from the official opinion of the RIVM or Dutch government I am not a regulator

2 REACH Registration, Evaluation, Authorisation and Restriction of CHemicals Registratie, Evaluatie en Autorisatie van CHemische stoffen Registrement, Evaluation et Autorisation des produits CHimiques Aims: Safety assessment for new and existing chemicals For existing chemicals in fact filling in of data gaps In less time, money and experimental animals Promotion of tests which do not use experimental animals. Optimal use of in vitro tests Stimulation of development of new in vitro tests Minimalization of test strategies

3 RIP 3.3 drafting group RIP 3.3 team for genetic toxicology and carcinogenicity Craig Boreiko (ILZRO, USA) Håkan Cederberg (KEMI, Sweden), Chair Rafaella Corvi (ECVAM, Italy) Lena Hellmér (KEMI, Sweden) Dinant Kroese (TNO, The Netherlands) PMG representative Cyrille Krul (TNO, The Netherlands) Jay Niemela (DFVF, Denmark) Stefan Pfuhler (P&G, Switzerland) Robert Priston (SHELL, UK) Andrew Smith (HSE, UK) Jan van Benthem (RIVM, The Netherlands)

4 Changes in the new guidance documents Existing data should at all levels be considered Some new tests were introduced in the strategy Possibilities to waive tests For tests using vertebrate animals there is a need to make a proposal to the European Chemicals Agency first To ensure that the number of animals is kept to a minimum testing in one sex only may be sufficient Possibility to waive positive and negative controls in in vivo genotoxicity tests Incorporation of genotoxicity tests in other (toxicity tests)

5 REACH REACH strategy is tonnage triggered 1 10 tpa Annex VII tpa Annexes VII and VIII tpa Annex VII, VIII and IX > 1000 tpa Annex VII, VIII, IX and X Annex VII VIII IX X GM test in bacteria (Ames) CA test in mammalian cells in vitro GM test in mammalian cells in vitro CA test in mammalian cells in vivo GM test in mammalian cells in vivo Germ cell mutagenicity test Carcinogenicity

6 Evaluation of the results genotoxicity test Regarding positive test results: Responses only at highly toxic/cytotoxic concentrations should be interpreted with caution. The presence or absence of a dose-response relationship should be considered. Regarding negative test results: Were the concentrations of test substance used high enough? Was the test system used sensitive to the nature of the genotoxic changes that might have been expected? Was test substance volatile? Was, for studies in vitro, the metabolic activation system active in the system? Was the test substance taken up by the test organism used for in vitro studies? Was, for studies in vivo, the substance reaching the target organ?

7 Evaluation of genotoxicity test Regarding contradictory test results : Conflicting results between non-mammalian and mammalian cell tests. The results of mammalian tests may be considered of higher significance. The results of indicator tests not supported by results obtained in tests for mutagenicity. The results of mutagenicity tests are generally of higher significance. Contradictory findings obtained in vitro and in vivo. In general, the results of in vivo tests indicate a higher degree of reliability. Contradictory findings due to the sensitivity and specificity of different test systems. The result from the test system known to produce more accurate responses should be given higher priority. Intra or inter laboratory variability for the same test. In this case, expert judgement should be used to reach an overall evaluation of the data. Other considerations: The purity of the test substance. The quality of a study. In compliance with the requirements stated in the guideline and/or GLP.

8 Chemical Metabolic etoxicification Metabolic activation metabolites DNA DNA damage (= pre-mutagenic lesion) DNA repair metabolites irreversible DNA modifications (= mutations) Excretion gene mutations numerical chromosome aberrations structural chromosome aberrations GGAAGTCTA CGT TCAGAT 2n +1 GGAAATCTA CGT TTAGAT genetic disease cancer

9 Annex VII ( tpa) Standard information required Specific rules for adaptation In vitro gene mutation study in bacteria. Further mutagenicity studies shall be considered in case of a positive result.

10 REACH strategy (February 2007) REACH Annex VII gene mutation test in bacteria - + normally no further testing at this level proceed with Annex VIII

11 Annex VIII ( tpa) Standard information required Specific rules for adaptation In vitro gene cytogenetic study in mammalian cells. In vitro gene mutation study in mammalian cells, if a negative result in Ames test (Annex V and Annex VI). The study does not usually need to be conducted if:. adequate data from an in vivo cytogenicity study are available or. the substance is known to be carcinogenic category 1 or 2 or mutagenic category 1,2 or 3. Study does not usually need to be conducted if adequate data from a reliable in vivo mammalian gene mutation test are available, Appropriate in vivo mutagenicity studies shall be considered in case of a positive result in any of the mutagenicity studies in Annex VII or VIII.

12 REACH strategy (February 2007) REACH Annex VII gene mutation test in bacteria - + normally no further testing at this level proceed with Annex VIII REACH Annex VIII REACH Annex VII micronucleus test in vitro or chromosome aberration test in vitro + + proceed with Annex IX - mouse lymphoma assay (tk +/- locus) or hprt assay - no further testing not genotoxic

13 Accuracy of combinations of in vitro tests Ames + Ames + Ames + Ames + MN CA MN + CA + MLA MLA Sensitivity Specificity Concordance / /626 50/74 193/298 Positive predictivity Negative predictivity Ames: MLA: MN: CA: Ames test mouse lymphoma assay micronucleus test chromosome aberration test Kirkland et al, 2005

14 Annex IX ( tpa) Standard information required Specific rules for adaptation If there is a positive result in any of the in vitro genotoxicity studies in Annex VII or IX, and there are no results available from an in vivo study already, an appropriate in vivo somatic cell genotoxicity study shall be proposed by the registrant. If there is a positive result in an in vivo somatic cell study available, the potential for germ cell mutagenicity should be considered on the basis of all available data, including toxicokinetic evidence. If no clear conclusions about germ cell mutagenicity can be made, additional investigations shall be considered.

15 Annex X (> 1000 tpa) Standard information required Specific rules for adaptation If there is a positive result in any of the in vitro mutagenicity studies in Annex VII or IX, a second in vivo somatic cell test may be necessary, depending on the quality and relevance of all the available data. If there is a positive result in an in vivo somatic cell study available, the potential for germ cell mutagenicity should be considered on the basis of all available data, including toxicokinetic evidence. If no clear conclusions about germ cell mutagenicity can be made, additional investigations shall be considered.

16 REACH strategy (February 2007) REACH Annexes IX and X REACH Annex VIII consider whether in vivo test is required check bioavailability check available data consider proper in vivo (follow up) test consider integration into other toxicity tests Evidence of genotoxicity is an indicator of potential carcinogenicity - testing complete not genotoxic - 2 nd in vivo test + 1 st in vivo test - check available data check for information on a genotoxic hazard to germ cells +

17 Germ cell tests Are they superfluous?? Do tests performed in somatic cells cover the risk on mutations in germ cells?? Heritable translocation or specific locus test insensitive Dominant lethal test points to chromosomal aberrations To cover induction of gene mutations in germ cells non guideline tests have to be performed, e.g. gene mutation test with transgenic mice Different tests for both sexes? Different tests for different stages of oogenesis and spermatogenesis?

18 REACH in vivo testing positive Annex IX en X germ cell mutagenicity testing Requirements: Consider all available information: available genotoxicity data read across non testing data If sufficient information is available to conclude that the substance may pose a hazard to germ cells, it can be concluded that the substance may cause heritable genetic damage and no further testing is justified. - assess toxicokinetic/dynamic profile and apply expert judgement - undertake toxicokinetic study If this information is lacking or inconclusive germ cell tests are necessary. - avoid heritable translocation or specific locus test - non guideline tests may be alternatives

19 REACH Annexes IX and X REACH Annex VIII REACH strategy (February 2007) consider whether in vivo test is required check bioavailability check available data consider proper in vivo (follow up) test consider integration into other toxicity tests Evidence of genotoxicity is an indicator of potential carcinogenicity - testing complete not genotoxic - 2 nd in vivo test + 1 st in vivo test - check available data check for information on a genotoxic hazard to germ cells sufficient + insufficient testing complete genotoxic in somatic and germ cells + + sufficient - germ cell genotoxicity test - - testing complete genotoxic in somatic cells

20 Germ cell mutagenicity testing Is all available testing & non-testing data information sufficient to decide on germ cell mutagenicity insufficient sufficient - sufficient + Genotoxic cat 2 Genotoxic cat 3 or - Consider integration of germ cell test in toxicity test(s) still to be performed Decide for tests in germ cells per se or tests to detect damage in offspring Choose tests on endpoint specificity gene mutation test in Tg mice - + Genotoxic cat 3 or - clastogenicity in rodent spermatogonial cells dominant lethal test comet assay Expanded Simple Tandem Repeat (ESTR) + - Genotoxic cat 2 Genotoxic cat 3 or -

21 Annex X (> 1000 tpa) Standard information required Specific rules for adaptation Carcinogenicity study. A carcinogenicity study may be proposed by the registrant or may be required by the Agency in accordance with Articles 39 or 40 if. the substance has a widespread dispersive use or there is evidence of frequent or long term human exposure; and. the substance is classified as mutagen cat 3 or there is evidence from the repeated dose study(ies) that the substance is able to induce hyperplasia and/or pre-neoplastic lesions. If the substance is classified as mutagenic category 1 or 2, the default presumption would be that a genotoxic mechanism for carcinogenicity is likely. In these cases, a carcinogenicity test will normally not be required.

22 Carcinogenicity testing vs classification as mutagen Cat 1 or 2 mutagen: positive in in vivo genotoxicity tests. in somatic cells. in germ cells (tests or existing data) Cat 3 mutagen: positive in in vivo genotoxicity tests. in somatic cells (concern for man owing to the possibility that they may induce heritable mutations in germ cells of humans)

23 REACH strategy (February 2007) REACH Annex VII - IX Non testing data & Other relevant information Annex VII: in vitro genotoxicity data Annex VIII: in vitro and in vivo genotoxicity data subacute toxicity data Note: Carcinogenicity should be considered at every tonnage level Annex IX: in vitro and in vivo genotoxicity data (sub-) chronic toxicity data reprotoxicity data Based on all available testing & non-testing data regard as carcinogen if the compound: is considered carcinogenic from existing data is in vivo genotoxic induces hyperplasia and/or (pre-)neoplastic lesions in repeated dose toxicity studies

24 Is all available testing & non-testing data information sufficient to decide on both C&L and risk characterisation? no yes REACH Annex X Consider integration of carcinogenicity indicators in toxicity test(s) still to be performed If no option or not informative Go through steps of scheme II of GDMF; in case of need of further testing, consider: in vitro assays (e.g. for grouping confirmation, SHE etc), short term carcinogenicity assay (e.g. transgenic mice etc) Decide on yes or no carcinogenic and if carcinogenic Decide on dose descriptor to be used in risk characterisation Information sufficient to decide on both C&L and risk characterisation? no Consider the conduct of a classical 2-year carcinogenicity test yes Note: A carcinogenicity test should be considered as a last resort.

25 Classification and Labelling Classification and labelling of (genotoxic) carcinogens: On the basis of the results of the classical carcinogenicity tests and/or epidemiological data Problems may occur when a classical carcinogenicity test has been waived Considerations for compounds: positive in genotoxicity tests - carc cat 3 with indications for carcinogenicity from other (sub-)chronic toxicity tests - carc cat 3 positive in a in vitro transformation assay - carc cat 3 positive in a short term carcinogenicity assay with Tg mice - carc cat 2

26 Risk assessment Risk assessment of (genotoxic) carcinogens: On the basis of the results of the classical carcinogenicity tests and/or epidemiological data Derivation of a DMEL (derived minimal effect level) Problems may occur when a classical carcinogenicity test has been waived Suggestions in the guidance document: Read across/category approach Use of (sub-)chronic studies Use of the Threshold of Toxicity Concept Other suggestions not in the guidance document: Use of in silico methods (PBPK) ALARA principle Use of the Lowest Observed Effect Dose (LOED) of genotoxicity studies

27 Summary Under the REACH regulation it is possible to test chemicals for genotoxicity and carcinogenicity in an efficient manner without endangering the safety of the product use. Implementation of REACH will not hamper classification and labelling for genotoxicity and carcinogenicity as long as this is not exclusively permitted on data from germ cell genotoxicity tests or a classical carcinogenicity assay, respectively. REACH may be incomplete as risk assessment for genotoxic carcinogens. Special attention should be given to integrated (or intelligent) test systems (ITS) to accelerate evaluations of chemicals and reduce the number of tests. It is questionable whether under REACH the costs, number of tests and above all the number of laboratory animals for genotoxicity testing will actually be reduced. Since (sub-)chronic and carcinogenicity studies, non genotoxic carcinogens may go undetected very easily.

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