Biomedical subjects

A M Hoberman

Publications and source records attributed to A M Hoberman.

At least 19 recordsLinked to original sources

PubMed2000

Lack of effects of nose-only inhalation exposure on testicular toxicity in male rats.

Reductions in testicular mass, sperm motility, and mating frequency have been attributed to the stresses caused by confinement of Sprague-Dawley male rats in nose-only inhalation exposure tubes. Testicular changes, including an increase in testicular atrophy, have been detected at an increased incidence in male rats used in inhalation studies as compared with rats of the same age and strain used in oral toxicity studies. This study was designed to determine whether nose-only exposure of male rats caused testicular toxicity under conditions of cooling of the exposure room and appropriate acclimation to the exposure tubes. In order to acclimate the rats to the nose-only inhalation exposure apparatus, all male rats were placed in the exposure tubes for at least four successively increasing time intervals (15, 30, 45, and 60 min) on 4 separate days, with a rest period of approximately 48 h between the first and second acclimation. Twenty male rats were exposed nose-only to filtered air for approximately 2 h per day for 28 days before cohabitation and continuing throughout a 14-day cohabitation period. To reduce thermal stress, the exposure room temperature was maintained at 64 to 70 degrees F. Twenty control rats were housed in the same room as the exposed rats but were not placed in exposure tubes. End points monitored were body weight, testicular weight, sperm count, sperm motility, and histopathology of the testes, epididymides, prostate, and seminal vesicles. The control rats gained weight more rapidly than the exposed rats. All the rats in both groups mated successfully, and testicular weights, normalized to body weight, were similar for both groups. More importantly, there were no microscopic changes that could be considered an adverse effect on the reproductive tissues in the male rats placed in exposure tubes. Thus, nose-only exposure for up to 2 h per day for a total of 42 days did not cause adverse effects on the reproductive organs, fertility, or reproductive performance of male rats under the conditions of this study.

Animals↗

PubMed2000

Lack of selective developmental neurotoxicity in rat pups from dams treated by gavage with chlorpyrifos.

Pregnant Sprague-Dawley rats were given chlorpyrifos (O:, O-diethyl-O:-[3,5,6-trichloro-2-pyridinyl] phosphorothioate; CPF) in corn oil by gavage from gestation day 6 (GD 6) through lactation day 10 (LD 10) at dosages of 0, 0.3, 1, or 5 mg/kg/day in a developmental neurotoxicity study that conformed to U.S. Environmental Protection Agency 1991 guidelines. GD 0 was the day when evidence of mating was observed and postnatal day 0 (PND 0) was the day of birth. Toxicity was limited to the highest dosage level (5 mg/kg/day) and, in the dams, consisted of muscle fasciculation, hyperpnea, and hyperreactivity. A nonsignificant overall trend toward weight gain and feed consumption was also observed in the high-dosage dams, with a statistically significant Group x Time interaction for reduced weight gain in the 5-mg/kg/day group near the end of gestation. Although many developmental indices were normal, pups from high-dosage dams had increased mortality soon after birth, gained weight more slowly than controls, and had several indications of slightly delayed maturation. The early deaths and delayed maturation were attributed to maternal toxicity, though a possible contributing role of direct pup toxicity in delayed development cannot be eliminated. In spite of the apparent delay in physical development, high-dosage pups tested just after weaning had normal learning and memory as tested on a T-maze spatial delayed-alternation task. Habituation, a primitive form of learning, was tested in 2 tasks (motor activity and auditory startle) and was not affected. No overt effects were noted in either dams or pups at 1 or 0.3 mg/kg/day. Based on these data, chlorpyrifos produced maternal and developmental toxicity in the 5-mg/kg/day-dosage group. There was no evidence of selective developmental neurotoxicity following exposure to chlorpyrifos.

Administration, Oral↗

PubMed1999

Developmental toxicity studies of four fragrances in rats.

Four fragrances, 6-acetyl-1,1,2,4,4,7-hexamethyltetraline (AHTN), 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-gamma-2-ben zopyran (HHCB), musk ketone and musk xylene were tested for developmental toxicity in Sprague-Dawley rats (25/group, 3 groups/fragrance, 2 fragrances/corn oil control). Dosages tested were HHCB: 50, 150, 500 mg/kg per day; AHTN: 5, 15, 50 mg/kg per day; musk ketone: 15, 45, 150 mg/kg per day; musk xylene: 20, 60, 200 mg/kg per day. All dosages tested exceeded multiples of the estimated maximal daily human dermal exposure. Treatment (gavage, 5 ml/kg) occurred on GDs 7-17 and Caesarean-sectioning on GD 20. Based on the results of these studies, none of the four fragrances tested were more toxic in the conceptuses than in the dams. Maternal NOAELs were 50, 5, 15 and 20 mg/kg per day for HHCB, AHTN, musk ketone and musk xylene, respectively (150, 50, 45 and 60 mg/kg per day caused clinical signs and reduced weight gain and feed consumption). Developmental NOAELs were 150, 50, 45 and 200 mg/kg per day for HHCB, AHTN, musk ketone and musk xylene, respectively. No adverse effects on embryo-fetal viability, growth or morphology occurred at the highest dosages of AHTN (50 mg/kg per day) or musk xylene (200 mg/kg per day). Developmental toxicity occurred at the high-dosages of HHCB (axial skeletal malformations at 500 mg/kg per day) and musk ketone (increased postimplantation loss and reduced fetal body weight at 150 mg/kg per day). The results of this study indicate that under conditions of normal use, the tested fragrances do not pose a risk to human conceptuses.

Animals↗

PubMed1999

Lack of developmental neurotoxicity of MN rgp 120/HIV-1 administered subcutaneously to neonatal rats.

The potential for neurotoxic effects was evaluated in rat off-spring after exposure in utero and/or during the neonatal period to a recombinant subunit vaccine of gp120 prepared from the MN strain of HIV-1 (MN rgp 120/HIV-1). Thirty pregnant female rats were given MN rgp120/HIV-1 with alum adjuvant, and 30 rats were given vehicle, once every 3 days from Day 1 of presumed gestation until parturition. One pup/sex/litter from treated and control group dams were given a daily subcutaneous injection, from Day 1 through Day 22 postpartum (PP) of vehicle, MN rgp120/HIV-1, MN rgp120/HIV-1 with alum, or MN rgp120/HIV-1 with QS-21 adjuvant. Neurobehavioral and physical development were evaluated (preweaning reflex and development, sexual maturation, motor activity, acoustic startle, passive avoidance, functional observational battery, and water M-maze testing), and tissues were processed for anatomical examination (whole and regional brain weights, and neuropathology). Administration of MN rgp120/HIV-1, with or without adjuvant, to pups did not cause any persistent effect on any parameter evaluated. Neurohistological examination did not reveal any pathological effects related to treatment. Thus, MN rgp120/HIV-1 alone or formulated as a vaccine does not cause neurotoxicity or developmental toxicity in neonatal rats after exposure in utero and/or during the neonatal period.

AIDS Vaccines↗

PubMed1998

Variability in the uterotrophic response assay (an in vivo estrogenic response assay) in untreated control and positive control (DES-DP, 2.5 microG/kg, bid) Wistar and Sprague-Dawley rats.

Inclusion of biological outlier values was found to bias the results of rat uterotrophic assays towards false negatives, i.e., not identify uterotrophic effects in treated populations. The present investigation was conducted to identify the background variability in the rat uterotrophic assay and to evaluate the need to exclude biological outlier values in untreated control groups. The Styrene Steering Committee (SSC) of the European Chemical Industry Council (CEFIC) co-sponsored this work with Argus Research Laboratories (Argus). The rat uterotrophic response assay originally was used as a pharmacology screen to identify estrogenic agents. Classically, 5 to 10 immature female rats (18 to 22 days of age) are administered an agent for three or four days. At sacrifice on the following day (21 to 26 days of age), the uterus is removed, weighed and a uterine weight/terminal body weight ratio calculated. This in vivo assay has been adapted for use in identifying the potential estrogenicity of chemicals, generally using 10 immature female rats per group, more closely controlling the ages, and adding one or more positive control groups to demonstrate sensitivity and response of the test system. Statistically significant increases in the positive control group means for absolute and relative uterine weights, as compared with the untreated (or vehicle-treated) means, is generally interpreted as identifying a sensitive test system. The untreated (and/or vehicle-treated) control group is then compared with the various test groups, and statistically significant increases in the mean absolute and relative uterine weights are identified as evidence of estrogenicity of the agent. Although not fully described previously, the inherent biological variability existing in both untreated and treated animals, can confound interpretation of the data, especially when numbers are relatively small. Our laboratories have identified that under controlled GLP-compliant conditions, some Wistar rats [randomly assigned (weight-ordered) to groups of ten at 22 +/- 1 days of age, and sacrificed when 26 +/- 1 days of age] in untreated control groups have high relative uterine weights that skew data distributions such that statistically significant differences are not present between untreated control and positive control groups. Based on these observations, further evaluations of untreated control and positive control (DES-DP, 2.5 micrograms/kg, b.i.d.) populations of three rat strains [Wistar--Chbb:THOM-SPF, Wistar--Crl:(WI)BR and Sprague-Dawley--Crl:CD(SD)IBS BR VAF/Plus "International Genetic Standard"] were made to define when such normal findings should be considered biological outliers, and whether outlier values should be excluded from analyses. Our data indicate that body weight is not always predictive of uterine weight, that relative uterine weight outlier values occur in each of these rat strains, and that statistically significant differences exist between groups of untreated control animals when outlier values are included in analyses. Of 98, 60 and 60 untreated control rats in the three respective strains, 11 (11.2%), 16 (26.7%) and 15 (25.0%) had relative uterine weights > or = 0.150%, and 5 (5.1%), 4 (6.7%) and 9 (15.0%) of these rats had relative uterine weights > or = 0.200%, values within the positive control range. All positive control rats attained relative uterine weights > or = 0.100%. Of 50, 60 and 60 positive control rats in the three respective rat strains, 27 (54%), 47 (78.3%) and 36 (60%) had relative uterine weights > or = 0.200%, 9 (18%), 2 (3.3%) and 7 (11.7%) had relative uterine weights > or = 0.300% and 5 (10%), 1 (1.7%) and 3 (5%) had relative uterine weights > or = 0.400%. The incidences of relative uterine weights > or = 0.300% in the positive control group may indicate the presence of high responders. Histological evaluations of uteri of positive control rats and untreated control rats with relative uterine weights > or = 0.

Animals↗

PubMed1998

Effect of dietary optimization on growth, survival, tumor incidences and clinical pathology parameters in CD Sprague-Dawley and Fischer-344 rats: a 104-week study.

Controversy regarding the use of ad libitum feeding in chronic rodent toxicity studies will soon result in issue of a FDA Points to Consider document. Caloric intakes are now recognized to be important uncontrolled variables in bioassays because rodents chronically fed ad libitum become obese, reproductively senile and have increased incidences of age-related diseases, higher tumor burdens and decreased survival. The available literature suggests that ad libitum feeding neither optimizes the health and well-being of rodents nor provides the best model for use in evaluation of pharmacological and toxicological profiles. Use of an optimized diet, restricted in terms of caloric intakes, has been proposed for chronic toxicity and carcinogenicity studies in rodents. It is suggested that limiting caloric intakes to 50-80% of ad libitum consumption would result in lower body weights, decreased tumor incidences and prolonged survival in the controls. To evaluate the influence of diet on chronic toxicity and carcinogenicity studies in rats, two 104-week studies were conducted. These studies consisted of 280 CD Sprague-Dawley and 280 Fischer-344 rats fed ad libitum, and 140 CD Sprague-Dawley and 140 Fischer-344 rats fed a diet that was optimized by limiting caloric intakes by 15-35%. Both diets consisted of certified commercial diet in meal form. The optimized diet reduced weight gain approximately 50% after 100 weeks. Clinical chemistry and hematology parameters showed negligible effects of reduced diet, with the exception that serum triglycerides were lower in males and females in both strains at weeks 52 and 104. The ad libitum-fed animals had a higher incidence of pseudopregnancy, aggressiveness, foot sores and abscesses than the animals fed an optimized diet. These effects were more pronounced in the CD Sprague-Dawley rats than in the Fischer-344 rats. At the completion of the 104-week study, survival in the ad libitum fed CD Sprague-Dawley rats was approximately one-half that of the animals fed an optimized diet (39% versus 76%). The difference in survival between Fischer-344 rats fed ad libitum and those fed an optimized diet was less pronounced (78% versus 89%). A reduced incidence of palpable tissue masses in the ad libitum-fed CD Sprague-Dawley rats versus the animals fed an optimized diet reflected inability to detect small masses in the obese ad libitum-fed animals. In contrast, the leaner Fischer-344 ad libitum-fed animals had an increased incidence of palpable tissue masses. After 52 weeks, 40 animals from each strain and feeding regimen were killed and subjected to complete necropsy and histopathological examination; the remainder of the survivors was examined at the completion of the study (104 weeks). Use of an optimized diet substantially reduced the incidences of endocrine-mediated tumors in both rat strains and delayed the onset of leukemia in Fischer-344 rats. These results indicate the need to further investigate the relationship of increased caloric intakes and endocrine-mediated or strain specific tumors and support FDA's and others' positions that use of diet optimization in chronic toxicity and carcinogenicity rodent bioassays has the potential to remarkably improve the scientific quality and relevance of these studies. It also identified that the small increases in cost associated with diet optimization are far exceeded by the advantages of increased survival of animals, reduced intercurrent disease and rumor burdens, and increased ease of histopathological processing and evaluation.

Animals↗

PubMed1996

Developmental toxicity of Exell, a surfactant mixture, in rats and rabbits.

A surfactant mixture (C.A.S No. 104559-06-2), is used in combination with foliar-acting herbicides to improve herbicidal performance by increasing plant uptake. It was administered by gavage as an aqueous solution to groups of 25 assumed pregnant Crl:CD BR rats from days 7-16 of gestation at daily dosage levels of 0, 3, 8, 20 or 50 mg/kg body weight. The dams were euthanized on Day 22 of gestation and the offspring were weighed and examined for external, visceral, and skeletal alterations. The surfactant mixture was maternally toxic at levels of 20 mg/kg/day and above as evidenced by reduced maternal weight gain and by an increased incidence of lung noise (wheezing and/or rattling) and sneezing. In addition, maternal food consumption was reduced in the high dosage group. There was no evidence of developmental toxicity at any dosage level. In the rabbit study, groups of 20 artificially inseminated adult Hra:(NZW)SPF rabbits were similarly dosed from Days 6-18 of gestation at daily dosage levels of 0, 12, 35, or 100 mg/kg body weight. The dose were euthanized on Day 29 of gestation and the offspring were weighed and examined for external, visceral, and skeletal alterations. Dosages of 35 and 100 mg/kg/day resulted in reduced maternal body weight gain, food consumption and fetal body weight. Thus, in the rat, the maternal and developmental no-observed-adverse-effect levels (NOAELs) were 8 mg/kg/day and greater than 50 mg/kg/day, respectively. In the rabbit, the maternal and developmental NOAELs were 12 mg/kg/day. This surfactant mixture was, therefore, not demonstrated to be uniquely toxic to either the rat or rabbit conceptus.

Abnormalities, Drug-Induced↗

PubMed1995

Developmental toxicity study of clarified slurry oil (CSO) in the rat.

Pregnant CD rats were exposed dermally to 0.05, 1, 10, 50, and 250 mg/kg/day of Clarified Slurry Oil (CSO) on Days 0-19 of gestation to determine its potential developmental toxicity. Untreated and vehicle controls were included in the study. Day 20 of gestation Caesarean-derived fetuses were examined for gross, external, and visceral or skeletal alterations. Dosages of 1 mg/kg/day and higher significantly decreased maternal body weight, body weight gain, feed consumption, gravid uterine weight, and live litter size and significantly increased resorption rate. These dosages also significantly reduced fetal weights and retarded development of the brain, kidney, thoracic and caudal vertebrae, metacarpals, and hindpaw phalanges in dosage groups with live fetuses (high dosage group dams resorbed all conceptuses). The 50- and 250-mg/kg/day dosage group dams had only placentas and/or dark red viscous fluid in the uterus or vagina and significant body weight loss (associated with resorption). The highest dosage also caused emaciation, slight dehydration, and swollen dark anogenital areas. These results indicate that CSO produces adverse developmental effects at maternally toxic dosages. The maternal and developmental NOAELs (no observed adverse effect levels) were 0.05 mg/kg/day. In a second study, groups of 10 mated female rats were exposed to "pulse" exposures and dosages of 1, 50, or 250 mg/kg/day of CSO applied dermally for 2- or 3-day intervals that spanned the gestation period. All dosages reduced maternal feed consumption and body weight gain during the treatment period. Dosages of 50 and 250 mg/kg/day also produced early resorptions when administered on Days 6 through 8 and 9 through 11 of gestation. However, no increase in fetal alterations occurred, indicating that the effects on embryo-fetal development were due to early death and not to the death of malformed conceptuses.

Abnormalities, Drug-Induced↗

PubMed1994

Interactive developmental toxicity of radiofrequency radiation and 2-methoxyethanol in rats.

Concurrent exposures to chemical and physical agents occur in the workplace; exposed workers include those involved with the microelectronics industry, plastic sealers, and electrosurgical units. Previous animal research indicates that hyperthermia induced by an elevation in ambient temperature can potentiate the toxicity and teratogenicity of some chemical agents. We previously demonstrated that combined exposure to radiofrequency (RF; 10 MHz) radiation, which also induces hyperthermia and is teratogenic to exposed animals, and the industrial solvent, 2-methoxyethanol (2ME), produces enhanced teratogenicity in rats. The present study replicates and extends the previous research investigating the enhanced teratogenicity of combined RF radiation and 2ME exposures. The interactive dose-related teratogenicity of RF radiation (sham exposure or maintaining colonic temperatures at 42.0 degrees C for 0, 10, 20, or 30 min) and 2ME (0, 75, 100, 125, or 150 mg/kg) was investigated by administering various combinations of RF radiation and 2ME to groups of rats on gestation days 9 or 13; gestation-day 20 fetuses were examined for external, skeletal, and visceral malformations. The results are consistent with and extend our previous research findings. Synergism was observed between RF radiation and 2ME for some treatment combinations, but not for others. The study also clarified which gestational periods, RF radiation exposure durations, and 2ME doses would be most informative in future interaction studies to determine the lowest interactive effect level. Day 9 exposures generally evidenced little effect by 2ME, either by itself or in combination with RF radiation. In contrast, day 13 exposures resulted in highly significant effects from 2ME and RF radiation. The structures showing strong evidence of effects from both 2ME and RF radiation after exposure on gestation day 13 were the forepaw digits, forepaw phalanges, hindpaw digits, hindpaw phalanges, hind limbs, metacarpals, and metatarsals. Statistical analyses did not show a global synergistic effect, but did show evidence for a synergistic effect at intermediate levels of the dose ranges. Future research will address potential interactions at lower doses.

Abnormalities, Drug-Induced↗

PubMed1994

[Reproductive and developmental toxicity studies of tazobactam/piperacillin or tazobactam(1)--Fertility and general reproduction study in rats with intraperitoneal administration].

Tazobactam (TAZ) is a newly developed beta-lactamase inhibitor and piperacillin (PIPC) is an antibiotics which is used in clinical field widely. The combination of TAZ and PIPC (TAZ/PIPC), which is combined with TAZ and PIPC at rate of 1:4, has been developed because of PIPC is unstable to various beta-lactamases. Fertility and general reproductive performance were studied in rats given daily intraperitoneal doses of TAZ/PIPC (200, 800 or 1600 mg/kg/day) or TAZ (40, 160 or 640 mg/kg/day). TAZ/PIPC or TAZ were given during premating period (70 days in males and 15 days in females), the pairing period (in males and females) and the gestation and lactation periods (in females). Total daily doses were administered in two equally divided doses. The study includes evaluation of the F1 generation and the F2 generation through weaning. In the TAZ/PIPC, maternal toxicity (decreased food consumption) was observed at 200 mg/kg and above dosage groups. At maternotoxic doses of 800 and 1600 mg/kg groups, increased resorptions, decreased live litter size, and increased fetal variations (reversible changes in ribs) were observed. Reversible delays in ossification of caudal vertebrae were also observed at 1600 mg/kg group. In the TAZ, maternal toxicities were observed at 160 mg/kg group (decreased food consumption) and 640 mg/kg group (decreased body weight gain and food consumption). Furthermore, necropsy (raised and/or colored areas present in the cecum) revealed slight increases at 40 mg/kg and above dosage groups. Slight decreases in implantations and resultant slight decreases in live litter size, reversible delays in renal development, and increased stillbirths were observed at 640 mg/kg group. Postnatal growth and development, behavior and reproductive performance of the F1 generation were not affected by the administration of TAZ/PIPC or TAZ. There were no effects on any of the fetal or pup parameters evaluated in the F2 generation. In conclusion, mating behavior and fertility were not affected by TAZ/PIPC or TAZ in this study. TAZ/PIPC or TAZ caused adverse change in reproductive performance of the F0 generation only at doses that caused maternal toxicity. The F1 and F2 generation were not affected.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1994

[Reproductive and developmental toxicity studies of tazobactam/piperacillin or tazobactam (2)--Teratological study in rats with intravenously administration].

Tazobactam (TAZ) is a newly developed beta-lactamase inhibitor and piperacillin (PIPC) is an antibiotics which is used in clinical field widely. The combination of TAZ and PIPC (TAZ/PIPC), which is combined with TAZ and PIPC at rate of 1:4, has been developed because of PIPC is unstable to various beta-lactamases. Teratogenic potential were studied in rats given daily intravenous doses of TAZ/PIPC (625, 1250, 2500 or 3750 mg/kg/day) or TAZ (125, 500 or 3000 mg/kg/day). TAZ/PIPC or TAZ were given from day 7 to day 17 of pregnancy. Total daily doses were administered in two equally divided doses. The study includes postnatal evaluation of the growth and development and reproductive performance of the F1 generation. Maternal deaths occurred in all groups given TAZ/PIPC. The incidence (range of 3 to 6 animals/group) was not dose dependent. Maternal body weight was decreased in rats receiving 3000 mg/kg of TAZ and food consumption was reduced in all drug-treated groups. Slight decreases in fetal body weights were observed at some doses that caused maternal body-weight or food-consumption decreases (2500 or 3750 mg/kg of TAZ/PIPC, 3000 mg/kg of TAZ). But these depressions of fetal body weights were not significant from control data. There were no fetal malformations or variations attributable to the test articles. Postnatal growth and development, behavior and reproductive performance of the F1 generation were not affected by the administration of TAZ/PIPC or TAZ. In conclusion, TAZ/PIPC or TAZ was not teratogenic in the rats. It is seemed that non-observed effect dose levels (NOELs) of TAZ/PIPC and TAZ for dams is less than 625 and 125 mg/kg/day in general toxicity respectively, however, NOELs of TAZ/PIPC is 3750 mg/kg/day or more and that of TAZ is 300 mg/kg/day or more for their offspring under the condition of this study.

Abnormalities, Drug-Induced↗

PubMed1994

[Reproductive and developmental toxicity studies of tazobactam/piperacillin or tazobactam (3)--Perinatal and postnatal study in rats with intraperitoneal administration].

Tazobactam (TAZ) is a newly developed beta-lactamase inhibitor and piperacillin (PIPC) is an antibiotics which is used in clinical field widely. The combination of TAZ and PIPC (TAZ/PIPC), which is combined with TAZ and PIPC at rate of 1:4, has been developed because of PIPC is unstable to various beta-lactamases. Perinatal and postnatal toxicity were studied in rats given daily intraperitoneal doses of TAZ/PIPC (200, 800 or 1600 mg/kg/day) or TAZ (40, 320 or 1280 mg/kg/day). TAZ/PIPC or TAZ were given from day 17 of pregnancy through day 21 of lactation. Total daily doses were administered in two equally divided doses. In this study, evaluation of the late stage of gestation, parturition, lactation and maternal behavior in adult rats and postnatal evaluation of the growth and development, and reproductive performance of the F1 generation occurred. In the TAZ/PIPC, maternal toxicity (decreased food consumption) was observed at 800 and 1600 mg/kg groups during perinatal period. A slight decrease in body weight gain during perinatal period and increased pup mortality and decreased pup weight in lactation period were observed at 1600 mg/kg group. An increase in stillbirths also was observed at 1600 mg/kg group. In the TAZ, maternal toxicity (decreased food consumption) was observed at all dosage groups during perinatal period. A decrease in body weight gain also were observed during perinatal period at 1280 mg/kg group. At maternotoxic doses of 320 and 1280 mg/kg groups, decreased pup weight were observed during lactation period. An increase in stillbirths also was observed at 1280 mg/kg group. Transient, significant decrease in pup body weights at 1280 mg/kg group in early postweaning period. No other effects occurred for the F1 generation rats. In conclusion, perinatal development and postnatal growth and development of offspring were affected only at the intermediate and high doses that caused maternal toxicity in this study. Therefore it is seemed that non-observed effect dose levels (NOELs) of TAZ/PIPC for dams is less than 200 mg/kg/day and that of TAZ is less than 40 mg/mg/day, and NOELs of TAZ/PIPC is 200 mg/kg/day and that of TAZ is 40 mg/kg/day for offspring under the condition of this study.

Animals↗

PubMed1993

Assessment of the reproductive toxic potential of dermally applied 2-hydroxy-4-methoxybenzophenone to male B6C3F1 mice.

The potential of 2-hydroxy-4-methoxybenzophenone (HMB) to cause male reproductive toxicity was assessed in B6C3F1 mice. HMB was administered topically for 13 weeks (5 days/week) to groups of 10 mice each at dosages of 0, 10, 20, 100, or 400 mg/kg/day. Additional high dosage and control mice were also included and euthanized at interim time points to characterize the time course of any effects. After 91 days (or at interim periods) mice were euthanized and reproductive organ weights, cauda epididymal sperm concentration and proportion of motile and abnormal sperm, and testicular spermatid concentration were determined. Testicular histology was evaluated in fixed tissue. HMB treatment had no effect on body weight gain or any of the male reproductive parameters assessed at any time point. These results indicate that topically applied HMB has no reproductive toxic potential in male B6C3F1 mice at dosages as high as 400 mg/kg/day.

Administration, Topical↗

PubMed1993

Developmental toxicity of acrolein in New Zealand white rabbits.

Pregnant New Zealand white rabbits (20 per group) were treated via stomach tube with 0.0, 0.1, 0.75, or 2.0 mg/kg/day from Days 7 through 19 of presumed gestation and subjected to cesarean sectioning on Day 29. Throughout the period of treatment, clinical observations, feed consumption, and body weights were recorded. At the termination of the study, reproductive and fetal parameters were measured. Three does died during the study, and transient effects on body weight gains and feed consumption were noted, with a subsequent rebound effect reflected in both fetal and maternal weights in the high-dose group (2 mg/kg/day). Resorptions were elevated in the high-dose group, but the effect was not statistically significant. Fetal malformations were distributed evenly among groups, and incidences were consistent with historical control data on the same strain and at the same laboratory. Higher dosage levels (range-finding study, 4.0 and 6.0 mg/kg/day) produced high incidences of maternal mortality, spontaneous abortion, resorptions, clinical signs, gastric ulceration, and/or sloughing of the gastric mucosa. Acrolein was not found to be a developmental toxicant or teratogen at doses not toxic to the does under the conditions employed in this study.

Abnormalities, Drug-Induced↗

PubMed1993

Critical developmental periods for effects on male rat genitalia induced by finasteride, a 5 alpha-reductase inhibitor.

The conversion of testosterone to 5 alpha-dihydrotestosterone by the enzyme 5 alpha-reductase is inhibited by finasteride. In a study in which maternal dosing with finasteride commenced on Gestational Day 15 and terminated on Postpartum Day 21, there were 13 and 27% decreases in anogenital distance of male pups on Postnatal Day 1 at 0.03 and 3 mg/kg/day, respectively. These decreases were largely reversed by Postnatal Day 22 even though treatment of the dams continued. Treatment at 3 mg/kg/day also resulted in hypospadias with cleft prepuce and a 5-day delay in the separation of the prepuce from the glans penis in those animals without hypospadias. A second study in which 20 mg/kg/day finasteride was administered on successive 2-day periods during late gestation in rats demonstrated that the period of Gestational Days 16 to 17 was the most sensitive (critical period) for finasteride-induced hypospadias, cleft prepuce, decreased anogenital distance, reduced prostate weight, and nipple formation in F1 male offspring. This critical period is just prior to the appearance on Day 18 of gestation of a midline mesenchymal plate between the urogenital sinus and the rectum in normal male fetuses. This midline plate does not appear in finasteride-exposed fetuses destined to have hypospadias as demonstrated in a previous study. Based on these observations, we hypothesize that finasteride causes hypospadias by preventing the formation of the medial mesenchymal plate which is necessary for assisting the movement of the urogenital sinus from the base to the tip of the genital tubercle.

5-alpha Reductase Inhibitors↗

PubMed1992

A decade of rabbit fertility data: study of historical control animals.

Reproductive data for 1795 artificially inseminated Hra: (NZW)SPF control rabbits in 93 developmental toxicity studies conducted from 1980 through 1989 were summarized. Data were obtained during terminal Caesarean-sectioning procedures performed on animals which survived to day 29 of gestation and during postmortem evaluation of does which aborted, delivered prematurely, or were found dead. Significant seasonal variation was not observed. Average pregnancy rate, percentage of rabbits that aborted, and percentage of rabbits that delivered prematurely throughout the decade were 86, 2.0, and 1.6%, respectively. Average numbers of corpora lutea, implantations, live fetuses, dead fetuses, early resorptions, and late resorptions for each doe that survived to scheduled termination were 10.8, 7.8, 7.1, 0.02, 0.49, and 0.15, respectively. The various vehicles used, routes of administration, and a variety of maternal and paternal factors were compared with the fertility data, and no correlations were observed. Rabbits that aborted earlier in gestation had fewer implantations than does which aborted late or delivered prematurely. Does which resorbed 100% of their conceptuses had fewer corpora lutea and implantations when compared with rabbits in the remainder of the population. Rabbits pregnant at scheduled termination which had a low number of corpora lutea or implantation sites had higher than expected pre- and postimplantation losses relative to the population as a whole. Does with a high number of corpora lutea had significantly higher preimplantation loss relative to the general population. This may indicate the presence of a "ceiling value" for the number of ova that can become fertilized and/or implant when the ovulation rate is high and which probably varies according to strain as well as a number of factors related to the individual rabbit. Based upon the results of this study and the work of a previous author, a minimum of four corpora lutea may be necessary for the successful maintenance of pregnancy in the New Zealand white rabbit. The minimum number of corpora lutea required may be strain dependent and may bear a relationship to the normal litter size of the strain.

Abortion, Veterinary↗

PubMed1992

Reproductive study of acrolein on two generations of rats.

Four groups of 30 male and 30 female rats were intubated with 70 daily doses of acrolein at levels of 0, 1, 3, or 6 mg/kg in a dosing volume of 5 ml/kg. Rats within each dosing group (F0 generation) were then assigned to a 21-day period of cohabitation and dosing for females continued through cohabitation gestation and lactation. Males were euthanized after cohabitation. F1 generation rats were chosen from pups, and a similar pretreatment, cohabitation, gestation, and lactation regimen was accomplished resulting in F2 generation pups. Reproductive parameters, body weights, food consumption, and clinical signs were recorded and necropsies were carried out on all treated animals. Histopathologic exams were accomplished on selected reproductive tissues. In addition, gross lesions, target tissues, stomachs, and lungs were examined. For the most part, reproductive parameters were unaffected by acrolein treatment with the exception of reduced pup weights in the F1 generation pups at the high-dose level (6 mg/kg/day). Gastric lesions were noted consistently in high-dose animals and some mid-dose (3 mg/kg/day) rats. Erosions of glandular mucosa and hyperplasia/hyperkeratosis of the forestomach were the most frequent stomach lesions observed. Effects on body weight gains were noted frequently for the high-dose animals and achieved statistical significance in the mid-dose animals on several occasions. Mortality in all high-dose animals was elevated relative to control animals. Acrolein, therefore, cannot be considered a selective reproductive toxin in the rat, but does produce toxicological effects down to a dosing level of 3 mg/kg/day.

Acrolein↗

PubMed1990

Developmental toxicity of orally administered 2',3'-dideoxycytidine in mice.

2',3'-Dideoxycytidine (DDC), a potent inhibitor of human immunodeficiency virus (HIV), is presently undergoing clinical trials as a promising anti-AIDS drug. Since there are very limited published animal toxicity data available, and nucleoside analogues are being considered for treatment of HIV-infected pregnant women, a study was conducted in mice to investigate the potential adverse developmental effects of this drug. DDC, suspended in 0.5% methyl cellulose, was administered via gavage twice per day during gestation days (gd) 6 through 15 to C57Bl/6N mice in a total dose of 0, 200, 400, 1,000, or 2,000 mg/kg/day. Maternal weight gain during the gestation and treatment period, as well as gravid uterine weight, decreased significantly in the 2,000 mg group, but weight gain, corrected for gravid uterine weight, was not affected by DDC. The percent resorptions per litter increased significantly in the highest dose group, and there were fewer live litters because of complete litter resorption in six dams. Among litters with live fetuses, the mean litter size was significantly reduced in the 2,000 mg group. Average fetal body weight per litter decreased significantly in the 1,000 and 2,000 mg groups. The number of fetuses with any malformation, the number of litters with one or more malformed fetuses and the percent of malformed fetuses per litter increased significantly in the 1,000 and 2,000 mg groups. There was an increase in malformations at 400 mg/kg/day; however, it was not statistically significant. In conclusion, DDC produced developmental toxicity (malformations, reduced fetal body weight, and resorptions) in the absence of overt maternal toxicity except for body weight changes due to resorptions and reduced fetal weights.

Animals↗