Retrospective analysis of relative parameter sensitivity in multi-generation reproductive toxicity studies

Current suggestions towards amending the OECD two-generation protocol include omission of the second generation and inclusion of additional parameters. This study analysed the relative parameter sensitivity in 18 individually published multi-generation studies with substances toxic to fertility. Amo...

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Bibliographic Details
Published in:Reproductive toxicology (Elmsford, N.Y.) N.Y.), 2009-09, Vol.28 (2), p.196-202
Main Authors: Dang, Zhi-Chao, Rorije, Emiel, Esch, Thijs Hogen, Muller, André, Hakkert, Betty C., Piersma, Aldert H.
Format: Article
Language:English
Subjects:
Animal Use Alternatives
Animals
Biological and medical sciences
Body Weight - drug effects
Classification and labelling
Continuous breeding
Dose-Response Relationship, Drug
Embryology: invertebrates and vertebrates. Teratology
European Union
Female
Fertility
Fundamental and applied biological sciences. Psychology
Genitalia - drug effects
Genitalia - pathology
LOAELs
Male
Medical sciences
Mice
OECD416
Offspring
Organ Size - drug effects
Rats
Reproduction - drug effects
Reproduction - physiology
Retrospective Studies
Risk Assessment
Sensitive reproductive endpoints
Sensitivity and Specificity
Teratology. Teratogens
Toxicity Tests - methods
Toxicity Tests - statistics & numerical data
Toxicology
Xenobiotics - classification
Xenobiotics - toxicity
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Summary:Current suggestions towards amending the OECD two-generation protocol include omission of the second generation and inclusion of additional parameters. This study analysed the relative parameter sensitivity in 18 individually published multi-generation studies with substances toxic to fertility. Among parameters that most often determined the reproductive LOAEL were weight of testis, dam and pup as well as litter size. Several other parameters were found to be unaffected in all studies evaluated. Some substances affected a specific set of parameters, indicating that rarely affected parameters may prove crucial in individual situations. This argues for the inclusion of a wide spectrum of parameters to cover all possible effects. Less sensitive parameters, mechanistically related to more sensitive ones, may be omitted as they will unlikely contribute to the overall LOAEL. This study gives first insights and needs follow-up by more extensive analyses before firm conclusions on the design of the two-generation study protocol can be drawn.
ISSN:0890-6238
1873-1708
DOI:10.1016/j.reprotox.2009.04.009