title: Evaluation of OECD screening tests 421 (reproduction/developmental toxicity screening test) and 422 (combined repeated dose toxicity study with the reproduction/developmental toxicity screening test).
abstract: The Advisory Committee on Existing Chemicals (BUA) of the Federal Republic of Germany convened a panel with expertise in reproductive and developmental toxicology to evaluate the OECD Screening Tests 421 (Reproduction/Developmental Toxicity Screening Test) and 422 (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test) with respect to their ability to unmask any potential toxic effects on reproduction. The original assignment for that panel was to "validate" those screening tests. However, the panel members recognized beforehand that this was actually an impossible task because of lack of a sufficient database. Only five chemicals with known reproductive toxicity had been examined following the OECD Screening Test Guidelines 421 or 422. A comparison of these test results with those of the definitive OECD Test Guidelines 414, 415, 416, or additional investigations could, therefore, only have been made with this very limited number of chemicals that had also undergone evaluation by one of the test guidelines cited. In each case biological properties relevant to reproductive toxicity were also indicated by the OECD Screening Tests 421 or 422. This communication reviews the main differences in study design of OECD Screening Test Guidelines 421 and 422 compared to those definitive test guidelines of similar study design for reproduction or developmental toxicity (especially with the one-generation study, OECD Test Guideline 415). The very limited possibilities of detecting late postnatal and postlactational manifestations are emphasized, as is the low statistical power of the OECD Screening Tests 421 and 422. Furthermore, the very limited ability to unmask teratogenicity is delineated. The outcome of screening tests was evaluated based on the results of 57 studies conducted according to the OECD Test Guideline 421 or 422. The test results were categorized according to the incidence of toxic effects on reproduction in the parent animals or their offspring and related to general toxic effects. Based on the ranking of these results, recommendations regarding setting rational priorities for further evaluations of existing chemicals' reproductive hazards are made. In general, the reviewer panel supports the OECD position that the screening tests are useful for initial hazard assessment and can contribute to the decision-making process on setting priorities for further test requirements. The panel also agrees with the OECD statement that the OECD Screening Tests 421 and 422 are neither an alternative to definitive tests (i.e., OECD Test Guidelines 414, 415, and 416) nor are they intended as their replacement.
authors.affiliation: BUA-Büro Munich, Technical University of Munich, Hohenbachernstrasse 15-17, 85350 Freising-Weihenstephan, Germany. ulrike.reuter@lrz.tum.de
authors.forename: Ulrike
authors.initials: U
authors.lastname: Reuter
authors.forename: Barbara
authors.initials: B
authors.lastname: Heinrich-Hirsch
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hellwig
authors.forename: Beate
authors.initials: B
authors.lastname: Holzum
authors.forename: Frank
authors.initials: F
authors.lastname: Welsch
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000175:diagnosis; D000818:Animals; D002648:Child; D002657:Child Development / Q000187:drug effects*; D005260:Female; D005333:Fetus / Q000187:drug effects; D005858:Germany; D017408:Guidelines as Topic; D015386:Hazardous Substances / Q000633:toxicity*; D006801:Humans; D011247:Pregnancy; D012098:Reproduction / Q000187:drug effects*; D018675:Toxicity Tests / Q000379:methods* / Q000592:standards*
chemical_list: D015386:Hazardous Substances