A Practical Approach, Second Edition=Ronald D. Ho.pdf

DEVELOPMENTAL AND REPRODUCTIVE TOXICITY STUDY FINDINGS 359Table 9.14Guideline-driven developmental and reproductive toxicity screens, by agencyGuideline NumberType of Screen EPA/OPPTS OECDPreliminary developmental toxicity screen (Chernoff-Kavlock assay) 870.3500 —Reproduction and developmental toxicity screening test 870.3550 421Combined repeated dose toxicity study with the reproduction and developmentaltoxicity screening test870.3650 422Table 9.15Selected features of developmental and reproductive toxicity screening studiesOPPTS 870.3550/ OPPTS 870.3650/OPPTS 870.3500 OECD 421 OECD 422Species Rat or mouse Rat or mouse Rat or mouseGroup size 15 females 10 per sex 10 per sexTreatment regimen GD 7 to 11 or toclosure of hardpalateMale: 28 daysFemale: 14 daysPremating through LD a 3Male: 28 daysFemale: 14 daysPremating through LD 3Toxicokinetics None None NoneMating period Not applicable Two weeksTwo weeks(bred prior to startof dosing)Behavioral testing None None FOB b motor activityOrgan weights None Testes, epididymides Testes, epididymides, liver, kidneys,adrenals, thymus, spleen, brain,heartHistopathology None Testes, epididymides,accessory sex organs,ovariesTestes, epididymides, accessory sexorgans, ovaries, uterus,gastrointestinal tract, urinary tract,lungs, central & peripheral nervoussystem, liver, kidneys, adrenals,thymus, spleen, heart, bone marrowPup necropsy Dead pups only External exam only External exam onlyNote: Additional subchronic endpoints: hematology, blood biochemistryaLactational day.bFunctional observational battery.in vivo screening guidelines for chemical evaluation and their respective requirements are presentedin Table 9.14 and Table 9.15. Another useful screen is the Reproductive Assessment by ContinuousBreeding (RACB) screen used routinely by the National Toxicology Program. 59While screening studies will identify potent toxicants if appropriate endpoints are includedand/or are correlated, Type I and Type II statistical errors can also result from the reduced samplesizes employed. The specificity of a screen refers to its capacity to produce false positives (TypeI error), while the sensitivity of a screen speaks to its ability to produce false negatives (Type IIerrors). The authors’ experiences with the Reproduction/Developmental Toxicity Screening Test(OECD 421/OPPTS 870.3550) and Combined Repeated Dose Toxicity Study with the Reproduction/DevelopmentalToxicity Screening Test (OECD 422/OPPTS 870.3650) confirm that theseerrors are not infrequent. In particular, these OECD and OPPTS screens are useful if employed astrue screens. However, they are not useful if they are considered apical studies for hazard identificationwhen there is significant potential for human exposure. An expert panel of the GermanChemical Society’s Advisory Committee on Existing Chemicals has concluded that OECD 421and 422 screening tests are neither alternatives to definitive studies (i.e., those conducted underOECD guidelines 414, 415, and 416) nor replacements for these studies, particularly because theplanned validation of these screening tests has not been completed. 60© 2006 by Taylor & Francis Group, LLC