The Himalayan rabbit (Oryctolagus cuniculus L.): spontaneous incidences of endpoints from prenatal developmental toxicity studies

Abstract

SummaryT he historical database represents the spontaneous, i.e. normal changes of charact ers, in laboratory animals, and is a must for the assessment of toxic effects of compounds. For the Himalayan rabbit (CHBB:HM , SPF) bac kground data were collected from the control groups of regulatory studies between 1968±1999 in the Biberach laboratory of Boehringer Ingelheim (Germany). In the present study these data were compared with the bac kground data from the years 1974±1984, with those from the Ingelheim laboratory, Germany (1977±1984) and those from the breeding colony at Kawanishi, Japan (1971±1991, 1972±1984 ).Fertilit y in the Biberach laboratory was relatively constant through the years, due to the strict breeding system. Litter parameters (corpora lutea, implantations and viabl e fetuses), including fetal sex distribution and fetal weight, were constant in the Biberac h laboratory through the years and compared well with the dat a from Ingelheim and Kawanishi.From these three laborat ories the results of spontaneous changes in fetal morphology above 0.1% incidence suggest a pattern of deviations from the Ba upla n (fundam ental body plan ). T hese comprise synosteosis of sternebrae, lumbar (additional ) ribs, hypoplasia of 12th rib, status of ossi®cation, aplasia of gall bladder, hypoplasia of gal l bladder, incompletely subdivided lung, dilated ventricle of heart, deviat ions at the A. carotis and at the aortic arch and¯exure of paw. T he absence of a time-dependent statistical trend indicates that the spontaneous change of endpoints remained constant through the tim e axis.Comparison with the spontaneously changed fetal morphology of the other strains (NZW, JW, SF rabbits ) does not provide support for their being a totally strain-speci®c pattern, and this pattern may be closer to the species than speci®c to a single strain. T he ®rm patterns of deviat ions in fetal morphology provide suitable and valuable markers for assessing toxic effects on ontogenesis. According to our experience these morphological endpoints react very sensitively to teratogenic compounds, which is dem onstrat ed by increased incidences. Our knowledge of evolution of organisms and of mechanisms leading to morphological deviations points to a strict selection of phenotypes. For laboratory anim als the decisive selection factors are de®ned by man. T hese are nutritive factors, environmental conditions, the mating system , handling and treatm ent, and experimental design. All these factors have to be held constant through the years, which is an absolute pre-condition for the applicati on of valid historical data.T he Himalayan rabbit is highly suitable for use in developmental toxicity studies due to the stability of reproductive data within the same laboratory over a period of more than 30 years, due to the similarity of reproductive data am ong three different laboratories, and due to an absence of relevant differences to the reproductive data of other rabbit strains.

Historical control data on prenatal developmental toxicity studies in rabbits

“…The average numbers of implantations and live fetuses were slightly higher than those of NZW rabbits reported by Kimmel and Price (1990) and Feussner et al. (1992) and of Himalayan rabbits reported by Viertel and Trieb (2003).…”

“…The values of reproductive parameters were not clearly different from those in previous surveys in Japan (Kameyama et al 1980;Morita et al 1987;Nakatsuka et al 1997). The average numbers of implantations and live fetuses were slightly higher than those of NZW rabbits reported by Kimmel and Price (1990) and Feussner et al (1992) and of Himalayan rabbits reported by Viertel and Trieb (2003). Tables S1 and S2 Tables S3 and S4, respectively.…”

“…Previously, historical control data on prenatal developmental toxicity studies are available for New Zealand White (NZW) rabbits (Palmer 1968; Kimmel and Price 1990; Feussner et al. 1992), Himalayan rabbits (Viertel and Trieb 2003), and Dutch Belted rabbits (Wise et al. 2009).…”

“…Historical control data may help to distinguish treatment-induced changes from spontaneous occurring background changes specific to the species/strains. Previously, historical control data on prenatal developmental toxicity studies are available for New Zealand White (NZW) rabbits (Palmer 1968;Kimmel and Price 1990;Feussner et al 1992), Himalayan rabbits (Viertel and Trieb 2003), and Dutch Belted rabbits (Wise et al 2009). In Japan, historical control data on reproductive and developmental toxicity studies in experimental animals including rabbits were reported by Kameyama et al (1980) (data from 13 laboratories), Morita et al (1987) (Japanese Pharmaceutical Manufacturer's Association (JPMA) survey, data between 1980 and 1985 from 52 laboratories), and Nakatsuka et al (1997) (JPMA survey, data between 1986 and 1993 from 71 laboratories).…”

Reproduktionstoxikologie

“…In den meisten Fällen werden die Wanderratte (R attus norvegicus Berkenhout) als Nager und das Kaninchen ( Oryctolagus cuniculus Linné) als Nichtnager eingesetzt. Kaninchen sind deutlich empfindlicher als Ratten gegenüber Teratogenen wie Thalidomid und daher für die Prüfung der toxischen Wirkung einer Prüfsubstanz auf die Embryonalentwicklung sehr gut geeignet. Warum zusätzlich die weniger empfindliche Ratte?…”