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The Need for Realism in Reproductive Toxicity Testing

The Need for Realism in Reproductive Toxicity Testing ATLA 36, 717, 2008 717 Susanne Bremer ECVAM, Institute for Health & Consumer Protection, European Joint Research Centre, 21020 Ispra (VA), Italy E-mail: susanne.bremer@jrc.it The purpose of the guest editorial (1), “Dev - macaques, marmosets, baboon and rhesus mon- elopmental and reproductive toxicity testing: a pot- keys. However, the teratogenic response to thalidomide is not uniform in the various species ted history”, is not clear to me. It described and justified the current situation in reproductive tox- to which its been applied. There are differences in icity testing in various regulatory frameworks, but the phenotypes of the malformations induced, as well as in the critical dosage. This is why current did not offer a critical assessment of what is really regulatory developmental toxicity testing is often needed to provide reliable data for safety assess- performed in a rodent and a non-rodent species. ment. It merely showed the historical development Finally, I must insist that it is embryonic devel- of regulatory guidelines and guidance. However, opment, rather than fetal development, which is there is now a need to critically consider whether the principal cause of concern, since organogenesis the testing paradigm is satisfactory, by retrospec- is the most sensitive phase in the developing child. tively analysing the existing data before applying I am sorry to have had to be so critical, but I the current scheme to large toxicological screening think it is important to spread the message that programmes, such as that represented by the EU there are opportunities for reducing the numbers REACH system. of animals used for reproductive/developmental The editorial does not reflect what is currently toxicity testing, not least via the development and needed, and there is no reference to the impor- application of intelligent testing strategies. In tance of relevant retrospective analysis. For exam- addition, with the support of the industry and the ple, Janer et al. (2), among others, have shown regulators, we should try to discover what are the that there is little added value in performing a sec- major target organs/toxic mechanisms involved ond generation in the two-generation study which with reproductive toxicants. If this information is currently requested by some regulators, e.g. in were available, the research would be much more the REACH system for high tonnage chemicals. focused and much more profitable, as a way of pro- The significance of reducing the numbers of ani- tecting our future generations. mals used by cutting out the second generation is enormous. A big effort is currently taking place at the OECD level to provide better study designs References that optimise the toxicological information pro- vided, by reducing animal use in reprotoxicity 1. Moxon, M. (2008). Developmental and reproductive evaluations. A new guideline is available and pub- toxicity testing: a potted history. Lab Animal Europe lic comments were invited up to 4 September 2008 8(3), 3. (3). Another example is the question of the added 2. Janer, G., Hakkert, B.C., Slob, W., Vermeire, T. & Piersma, A.H. (2007). A retrospective analysis of the value of including a second species in developmen- two-generation study: what is the added value of the tal toxicity testing. I think the editorial should also second generation? Reproductive Toxicology 24, have included a critical appraisal of the newest 97–102. activities in this area (4). It would also have been 3. Anon. (2008). DRAFT Extended One-Generation interesting for the reader to be provided with some Reproductive Toxicity TEST GUIDELINE, 37pp. data on how many animals are used, for example, Paris, France: OECD. Available at: http://www.oecd. org/dataoecd/22/20/40899803.pdf (Accessed 28.07.08). in a two-generation study and in a developmental 4. Janer, G., Slob, W., Hakkert, B.C., Vermeire, T. & neurotoxicity (DNT) study, the two most animal- Piersma, A.H. (2008). Retrospective analysis of devel- intensive study designs in current use. opmental toxicity studies in rat and rabbit: what is The author refers to the thalidomide tragedy. the added value of the rabbit as an additional test The editorial implies that thalidomide causes sim- species? Regulatory Toxicology & Pharmacology 50, ilar defects in mice, rats, hamsters, rabbits, 206–217. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Alternatives to Laboratory Animals SAGE

The Need for Realism in Reproductive Toxicity Testing

Bremer, Susanne
Alternatives to Laboratory Animals , Volume 36 (6): 1 – Dec 1, 2008
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References (3)

Publisher
SAGE
Copyright
© 2008 Fund for the Replacement of Animals in Medical Experiments
ISSN
0261-1929
eISSN
2632-3559
DOI
10.1177/026119290803600617
Publisher site
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Abstract

ATLA 36, 717, 2008 717 Susanne Bremer ECVAM, Institute for Health & Consumer Protection, European Joint Research Centre, 21020 Ispra (VA), Italy E-mail: susanne.bremer@jrc.it The purpose of the guest editorial (1), “Dev - macaques, marmosets, baboon and rhesus mon- elopmental and reproductive toxicity testing: a pot- keys. However, the teratogenic response to thalidomide is not uniform in the various species ted history”, is not clear to me. It described and justified the current situation in reproductive tox- to which its been applied. There are differences in icity testing in various regulatory frameworks, but the phenotypes of the malformations induced, as well as in the critical dosage. This is why current did not offer a critical assessment of what is really regulatory developmental toxicity testing is often needed to provide reliable data for safety assess- performed in a rodent and a non-rodent species. ment. It merely showed the historical development Finally, I must insist that it is embryonic devel- of regulatory guidelines and guidance. However, opment, rather than fetal development, which is there is now a need to critically consider whether the principal cause of concern, since organogenesis the testing paradigm is satisfactory, by retrospec- is the most sensitive phase in the developing child. tively analysing the existing data before applying I am sorry to have had to be so critical, but I the current scheme to large toxicological screening think it is important to spread the message that programmes, such as that represented by the EU there are opportunities for reducing the numbers REACH system. of animals used for reproductive/developmental The editorial does not reflect what is currently toxicity testing, not least via the development and needed, and there is no reference to the impor- application of intelligent testing strategies. In tance of relevant retrospective analysis. For exam- addition, with the support of the industry and the ple, Janer et al. (2), among others, have shown regulators, we should try to discover what are the that there is little added value in performing a sec- major target organs/toxic mechanisms involved ond generation in the two-generation study which with reproductive toxicants. If this information is currently requested by some regulators, e.g. in were available, the research would be much more the REACH system for high tonnage chemicals. focused and much more profitable, as a way of pro- The significance of reducing the numbers of ani- tecting our future generations. mals used by cutting out the second generation is enormous. A big effort is currently taking place at the OECD level to provide better study designs References that optimise the toxicological information pro- vided, by reducing animal use in reprotoxicity 1. Moxon, M. (2008). Developmental and reproductive evaluations. A new guideline is available and pub- toxicity testing: a potted history. Lab Animal Europe lic comments were invited up to 4 September 2008 8(3), 3. (3). Another example is the question of the added 2. Janer, G., Hakkert, B.C., Slob, W., Vermeire, T. & Piersma, A.H. (2007). A retrospective analysis of the value of including a second species in developmen- two-generation study: what is the added value of the tal toxicity testing. I think the editorial should also second generation? Reproductive Toxicology 24, have included a critical appraisal of the newest 97–102. activities in this area (4). It would also have been 3. Anon. (2008). DRAFT Extended One-Generation interesting for the reader to be provided with some Reproductive Toxicity TEST GUIDELINE, 37pp. data on how many animals are used, for example, Paris, France: OECD. Available at: http://www.oecd. org/dataoecd/22/20/40899803.pdf (Accessed 28.07.08). in a two-generation study and in a developmental 4. Janer, G., Slob, W., Hakkert, B.C., Vermeire, T. & neurotoxicity (DNT) study, the two most animal- Piersma, A.H. (2008). Retrospective analysis of devel- intensive study designs in current use. opmental toxicity studies in rat and rabbit: what is The author refers to the thalidomide tragedy. the added value of the rabbit as an additional test The editorial implies that thalidomide causes sim- species? Regulatory Toxicology & Pharmacology 50, ilar defects in mice, rats, hamsters, rabbits, 206–217.

Journal

Alternatives to Laboratory Animals – SAGE

Published: Dec 1, 2008

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