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Impact of positive carcinogenicity findings on strategies of genotoxicity follow-up testing
Abstracts / Toxicology Letters 172S (2007) S1–S240
been confirmed in in vivo genotoxicity and/or carcinogenicity studies, raising the question of their specificity and relevance in human risk assessment. Positive in vitro results generally lead to costly and time consuming additional testing, including mechanistic studies and in vivo genetic toxicity testing in rodent models. In the context of regulating pharmaceuticals, pesticides or industrial chemicals, such positive in vitro results could potentially lead to prohibiting the use and/or development of compounds of negligible concern for adverse human effects. It is increasingly accepted that positive results should not be considered in isolation, and that a weight of evidence approach considering all pertinent data should be preferred. Several current initiatives, including the one recently launched by the ILSI Health and Environmental Sciences Institute (HESI), highlight the willingness of scientists from various sectors to (1) change and improve testing, data interpretation and the current paradigm, and (2) to move from a hazard identification approach to a “realistic” risk-based approach that incorporates information on mechanism of action, kinetics, and human exposure.
S25
tigating genotoxicity in the tumor target organ(s) are highly recommended. Transgenic gene mutation assays, the comet assay or DNA binding studies are considered equally appropriate for this purpose. Negative findings in this stage of testing increase the confidence in assuming that the MOA is probably not associated with genotoxicity and the possibility of other MOAs should be reconsidered. The question of what is sufficient negative genotoxicity test data to establish that a carcinogen does not act by a genotoxic MOA, when plausible information on a specific non-genotoxic MOA are lacking, is difficult to answer. doi:10.1016/j.toxlet.2007.05.091 S11 Endocrine Disruptors in the Environment: Increasing the Specificity of Detection of Endocrine Activity 59 Endocrine active substances in consumer products: Significance of screening assay results Thomas H. Broschard 1 , Gerhard J. Nohynek 2
doi:10.1016/j.toxlet.2007.05.090 58 Impact of positive carcinogenicity findings on strategies of genotoxicity follow-up testing Peter Kasper Federal Institute for Drugs and Medical Devices, Bonn, Germany The distinction between genotoxic versus non-genotoxic modes of actions (MOA) plays a fundamental role in the manner chemicals are handled in the regulatory arena, particularly for the selection of an appropriate dose response relationship for the extrapolation of animal tumor findings to low exposure levels usually seen for humans. This presentation will focus on recommendations developed at the IWGT 2005 in San Francisco on how to proceed in the MOA evaluation of a rodent carcinogen when a standard battery of genotoxicity tests is negative, but yet no plausible nongenotoxic MOA is apparent. The decision whether to direct the testing strategy towards genotoxicity or nongenotoxicity endpoints should be based on a thorough weight of the evidence evaluation of all relevant information including structure-activity relationship analysis, target organ-specific metabolic profile and nature of the tumor findings. If this step of assessment identifies a need for further genotoxicity testing, test models for inves-
1 Merck
KGaA, Institute of Toxicology, 64293 Darmstadt, Germany; 2 L’Oreal R&D, Worldwide Safety Evaluation, 92600 Asni`eres, France The International Program on Chemical Safety (IPCS) defined endocrine disruptors in 2004 as exogenous substances that cause adverse health effects in the intact organism or its progeny, secondary/consequent to changes in endocrine function. Today, the term endocrine disruptor has been widely misapplied to label substances with slight, hormone-like activity discovered in research laboratories utilizing in vitro or in vivo screening assays. Over the past years an increasing number of substances with slight estrogenic activity were identified in consumer products such as UV-filters, preservatives, fragrances, emollients and biocides. Frequently, screening assays were used not only to identify an endocrine activity but also to imply a possible risk to human health. For instance, the ultraviolet filter 4-methylbenzylidene camphor (4-MBC) was reported to have weak estrogenic activity in screening assays resulting in considerable media attention and significant public health concerns. Subsequently published studies on 4-MBC suggested adverse effects on male fertility. However, when these studies were repeated in robust reproductive toxicity studies, their results could not be reproduced. No adverse reproductive effects were found up to the highest 4-MBC levels tested. 4-MBC has minimal estrogenic potency, when compared with that of human endogenous hor-
been confirmed in in vivo genotoxicity and/or carcinogenicity studies, raising the question of their specificity and relevance in human risk assessment. Positive in vitro results generally lead to costly and time consuming additional testing, including mechanistic studies and in vivo genetic toxicity testing in rodent models. In the context of regulating pharmaceuticals, pesticides or industrial chemicals, such positive in vitro results could potentially lead to prohibiting the use and/or development of compounds of negligible concern for adverse human effects. It is increasingly accepted that positive results should not be considered in isolation, and that a weight of evidence approach considering all pertinent data should be preferred. Several current initiatives, including the one recently launched by the ILSI Health and Environmental Sciences Institute (HESI), highlight the willingness of scientists from various sectors to (1) change and improve testing, data interpretation and the current paradigm, and (2) to move from a hazard identification approach to a “realistic” risk-based approach that incorporates information on mechanism of action, kinetics, and human exposure.
S25
tigating genotoxicity in the tumor target organ(s) are highly recommended. Transgenic gene mutation assays, the comet assay or DNA binding studies are considered equally appropriate for this purpose. Negative findings in this stage of testing increase the confidence in assuming that the MOA is probably not associated with genotoxicity and the possibility of other MOAs should be reconsidered. The question of what is sufficient negative genotoxicity test data to establish that a carcinogen does not act by a genotoxic MOA, when plausible information on a specific non-genotoxic MOA are lacking, is difficult to answer. doi:10.1016/j.toxlet.2007.05.091 S11 Endocrine Disruptors in the Environment: Increasing the Specificity of Detection of Endocrine Activity 59 Endocrine active substances in consumer products: Significance of screening assay results Thomas H. Broschard 1 , Gerhard J. Nohynek 2
doi:10.1016/j.toxlet.2007.05.090 58 Impact of positive carcinogenicity findings on strategies of genotoxicity follow-up testing Peter Kasper Federal Institute for Drugs and Medical Devices, Bonn, Germany The distinction between genotoxic versus non-genotoxic modes of actions (MOA) plays a fundamental role in the manner chemicals are handled in the regulatory arena, particularly for the selection of an appropriate dose response relationship for the extrapolation of animal tumor findings to low exposure levels usually seen for humans. This presentation will focus on recommendations developed at the IWGT 2005 in San Francisco on how to proceed in the MOA evaluation of a rodent carcinogen when a standard battery of genotoxicity tests is negative, but yet no plausible nongenotoxic MOA is apparent. The decision whether to direct the testing strategy towards genotoxicity or nongenotoxicity endpoints should be based on a thorough weight of the evidence evaluation of all relevant information including structure-activity relationship analysis, target organ-specific metabolic profile and nature of the tumor findings. If this step of assessment identifies a need for further genotoxicity testing, test models for inves-
1 Merck
KGaA, Institute of Toxicology, 64293 Darmstadt, Germany; 2 L’Oreal R&D, Worldwide Safety Evaluation, 92600 Asni`eres, France The International Program on Chemical Safety (IPCS) defined endocrine disruptors in 2004 as exogenous substances that cause adverse health effects in the intact organism or its progeny, secondary/consequent to changes in endocrine function. Today, the term endocrine disruptor has been widely misapplied to label substances with slight, hormone-like activity discovered in research laboratories utilizing in vitro or in vivo screening assays. Over the past years an increasing number of substances with slight estrogenic activity were identified in consumer products such as UV-filters, preservatives, fragrances, emollients and biocides. Frequently, screening assays were used not only to identify an endocrine activity but also to imply a possible risk to human health. For instance, the ultraviolet filter 4-methylbenzylidene camphor (4-MBC) was reported to have weak estrogenic activity in screening assays resulting in considerable media attention and significant public health concerns. Subsequently published studies on 4-MBC suggested adverse effects on male fertility. However, when these studies were repeated in robust reproductive toxicity studies, their results could not be reproduced. No adverse reproductive effects were found up to the highest 4-MBC levels tested. 4-MBC has minimal estrogenic potency, when compared with that of human endogenous hor-