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

PERSPECTIVES ON THE DEVELOPMENTAL AND REPRODUCTIVE TOXICITY GUIDELINES 749Table 19.7Comparison of current guidelines for the postnatal and behavioral assessmentsGuideline ICH 4.1.2 a EPA OPPTS 870.6300 b Book cFDA RedSpecies (No.)MatingRoute of testcompoundadministrationExposure to testcompoundProcedures on testanimalsAt least one species,preferably ratsPlug, sperm, orinsemination is day 0Similar to the route usedby humansFrom implantation to theend of lactationFemales deliver and rearoffspring to weaning;select oneweanling/sex/litter toassess reproductivecompetenceMaternal observations:clinical signs, bodyweight, and feedconsumptionNecropsy: all adults,preserve organs withmacroscopic findingsfor possible histologicalevaluation;implantations,abnormalities inoffspring, live or deadoffspring at birth, bodyweight at birth, pre- andpostweaning survivaland growth and bodyweight, maturation andfertility, physicaldevelopment, sensoryfunctions, reflexes, andbehaviorOECD dApproximately 20 pregnant rats incontrol group; similar numbers formating pairs in treatment groups— —Mate females with males of the— —same strain and species (plug orsperm is day 0)Oral (diet, drinking water, or gavage) — —From implantation through day 10postnatallyDams: detailed clinical observations,including assessment of signs ofautonomic function; description ofabnormal movements, posture,gait, and behavior, etc.; bodyweights (at least weekly, day ofdelivery, and PDs 11 and 21)Observation of offspring: dailycageside observations (PDs 4, 11,21, 35, 45, and 60) for gross signsof mortality or morbidityDevelopmental landmarks: countand weigh live pups (PDs 0, 4, 7,14, and 21, then every 2 weeks)and assess sexual maturation; cullon PD 4Behavior: learning and memory(weaning and adulthood), motoractivity (PDs 13, 17, 21, and60 ± 2), auditory startle (PDs 22and approximately PD 60)Neuropathology: on PND 11 and attermination, remove and weighbrains of 1 pup/sex/litter (total10/sex/dosage group), then select6 pups/sex/dose forneuropathological evaluation— —— —aFDA, Fed. Regist., 59(183), 1994.bPostnatal assessments are covered in the EPA OPPTS 870.6300 Development Neurotoxicity study and EPAOPPTS 870.3800 multigeneration guideline.cPostnatal assessments are covered in the FDA “Redbook” two generation guideline.dPostnatal assessments are covered in the OECD 415 and 416 multigeneration guidelines PND(s) = day(s)postnatal.toxicity studies. As noted for male animals, reduced fertility may have many causes, and theproduction of a litter is not sufficient to assume the absence of an effect on reproductive performance.Rats and mice generally have multiple intromissions in one copulatory interval, and such activitygenerally is associated with improved fertility in the females. Should it appear that aberrant copulatorybehavior is present, videotaping the animals and grading the numbers of copulations (matings) andintromissions, duration of intromission, and expected female receptivity (lordosis) is recommended.The ICH guidelines do not identify specific methods for performing the sperm evaluations,while EPA protocols require evaluation of specific parameters by recommended methodologies,generally including automated sperm evaluations. There are two generally used automated techniques,the Cellsoft System and the Hamilton Thorne System. While the Cellsoft system had themost advanced technical capacity, and hand methods are sufficient to meet the guideline requirements,86,87 the Hamilton Thorne System has become that most widely used.© 2006 by Taylor & Francis Group, LLC