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Biomedical subjects

M K Smith

Publications and source records attributed to M K Smith.

At least 73 records · Page 4Linked to original sources
PubMed1988

Teratogenic effects of trichloroacetonitrile in the Long-Evans rat.

Trichloroacetonitrile (TCAN) is among a number of contaminants found in drinking water produced by reactions of chlorine with background organic material. Long-Evans rats were intubated with TCAN (0, 1, 7.5, 15, 35, 55 mg/kg) in a tricaprylin vehicle on gestation days 6-18. The highest dose tested (55 mg/kg) was lethal in 21% of the dams and produced 100% resorptions in two-thirds of the survivors. Only one maternal death was seen at the next-lower dose; however, fetal weight and viability were decreased in a dose-related manner. The percentage of embryolethality was 13.9% at the lowest dose and 78.4% at the high dose, with resorption of entire litters seen at 7.5 mg/kg and above. At all doses, cardiovascular (interventricular septal defect, levocardia, common carotid, and right-sided aortic arch and ductus arteriosus) and urogenital (hypoplastic, missing, misplaced and fused kidneys, and hypoplastic uterine horns) malformations were seen in the offspring. Frequency of these malformations was dose related, ranging from 8% to 35% at the 1.0- and 35-mg/kg doses, respectively. The incidence of total soft tissue malformations was statistically significant at 15 and 35 mg/kg. There were no significant treatment-related changes in the incidence of skeletal malformations. The no-effect dose was established by statistical analysis to be 1.0 mg/kg/day.

Abnormalities, Drug-Induced↗
PubMed1988

Nitrite-induced iron deficiency in the neonatal rat.

Neonatal rats from dams receiving 2 or 3 g NaNO2/liter in the drinking water through -gestation and lactation suffered severe microcytic anemia as well as growth retardation and high mortality. Lipemia, fatty liver damage, decreased erythropoiesis of spleen and bone marrow, and reduced plasma and tissue iron levels were noted in affected pups. These effects were all consistent with and characteristic of iron deficiency. Experiments presented here were designed to show that the maternally mediated toxicity of nitrite is actually an iron deficiency syndrome in the pups caused by inadequate iron transfer from dam to pup. It was found that administration of exogenous iron supplement to pups of treated mothers reversed the anemia and other effects of nitrite toxicity noted both in previous studies and in unsupplemented littermates. Mothers of affected pups were themselves anemic. Finally, we fully documented severe iron deficiency in pups of nitrite-treated mothers and showed that these mothers produced milk of reduced iron content. It appears then that nitrite-consuming dams have a reduced capacity to transfer iron to their pups. The nitrite-associated toxicities in the pups are actually a result of an iron deficiency.

Anemia↗
PubMed1987

Developmental toxicity of halogenated acetonitriles: drinking water by-products of chlorine disinfection.

The developmental toxicity of acetonitrile and 5 halogenated derivatives was examined with an in vivo teratology screen adapted for use in the Long-Evans rat. The screen was extended to an evaluation of growth till postnatal Days 41-42, and weight of several organs at sacrifice. Acetonitrile was without developmental effects even at doses toxic to the dam. Of the halogenated compounds, treatment with trichloroacetonitrile (TCAN) and dichloroacetonitrile (DCAN) resulted in reduced fertility and increased early implantation failure. There was no effect on litter size in females bearing live litters, but pup birth weight was reduced in all litters exposed to halogenated compounds. Perinatal survival of the pups was adversely impacted by DCAN and TCAN. Postnatal growth till Day 4 was reduced by DCAN and bromochloroacetonitrile (BCAN) while growth till Day 42 was consistently affected only by TCAN. Some general observations were made on the usefulness of the criteria used in the screen, and TCAN, the most toxic of the halogenated compounds, was selected for further in-depth evaluation.

Abnormalities, Drug-Induced↗
PubMed1987

Evaluation of the teratogenic effects of Tri-ortho-cresyl phosphate in the Long-Evans hooded rat.

The developmental toxicity of tri-ortho-cresyl phosphate (TOCP) was evaluated in Long-Evans rats. Pregnant rats were treated with 87.5, 175, and 350 mg/kg/day TOCP throughout organogenesis from gestation Days 6 through 18 (Day of sperm = Day 0). The highest dose tested (350 mg/kg) was lethal in 28% of the dams; no maternal deaths or toxicity were observed in the 87.5 or 175 mg/kg dose groups. There were no significant differences noted among the experimental and control groups for preimplantation loss or resorption. Fetal weights for both sexes in the TOCP groups were significantly greater than in the control group; however, no difference among the TOCP groups was observed. Malformation rates were too low to warrant statistical analysis. Numerous soft tissue and skeletal variations were observed in both control and TOCP-treated groups; there were no significant differences in the frequency of variations among the dose groups. The results of this study indicate that TOCP is not teratogenic in the Long-Evans rat.

Abnormalities, Drug-Induced↗
PubMed1987

Evaluation of the developmental toxicity of sodium nitrite in Long-Evans rats.

Sodium nitrite administered in the drinking water to Long-Evans rats during pregnancy and lactation severely affected erythropoietic development, growth, and mortality in their offspring. Pregnant rats were maintained throughout gestation on 0.5, 1, 2, or 3 g NaNO2/liter. There were no significant differences between treated and control litters at birth. Thereafter, pups of treated dams on 2 and 3 g NaNO2/liter gained less weight, progressively became severely anemic, and began to die by the third week postpartum. By the second week postpartum, hemoglobin levels, RBC counts, and mean corpuscular volumes of these pups were all drastically reduced compared to controls. Blood smears showed marked anisocytosis and hypochromasia. Gross chylous serum lipemia and fatty liver degeneration were noted. Histopathology demonstrated cytoplasmic vacuolization of centrilobular hepatocytes and decreased hematopoiesis in bone marrow and spleen. Administration of 1 g NaNO2/liter resulted in hematological effects but did not affect growth or mortality. NaNO2 (0.5 g/liter) was at or near the no observed effect level. Cross-fostering indicated that treatment during the lactational period was more instrumental in producing lesions than treatment during the gestational period. The data presented are consistent with the lactational induction of severe iron deficiency in the neonate.

Animals↗
PubMed1987

Examination of the reproductive effects of tricresyl phosphate administered to Long-Evans rats.

Tricresyl phosphate (TCP) is used commercially as a plasticizer and a flame retardant. The reproductive effects of TCP (less than 9.0% TOCP) were examined. Male Long-Evans rats received 0, 100, or 200 mg/kg and females received 0, 200, or 400 mg/gk TCP in corn oil by gavage. The 100 mg/kg TCP males were mated with 200 mg/kg TCP females, and 200 mg/kg TCP males were bred with 400 mg/kg TCP females. Males were dosed for 56 days and females for 14 days prior to breeding and throughout the 10-day breeding period. Following breeding, the males were necropsied and evaluated for sperm parameters and reproductive tract histopathology. Females were dosed throughout gestation and lactation. Pups and adult females were necropsied on postnatal day 21. Sperm concentration, motility, and progressive movement were decreased for 200 mg/kg dose group males. A dose-dependent increase in abnormal sperm morphology was observed for males in both TCP dose groups. The percent of sperm-positive females per group was unchanged, but the number of females delivering live young was severely decreased by TCP exposure. Litter size and pup viability were decreased in the 400 mg/kg dose group. Pup body weight and developmental landmarks were unaffected by TCP exposure. Histopathologic changes were observed in the testes and epididymides of male rats and in the ovaries of female rats exposed to TCP.

Animals↗
PubMed1987

Sodium chlorite administration in Long-Evans rats: reproductive and endocrine effects.

Long-Evans rats, 4-6 weeks of age, were given access to 0, 1, 10, or 100 ppm sodium chlorite in deionized water ad libitum as drinking water. Males were exposed 56 days, and females for 14 days prior to breeding and throughout the 10-day breeding period. Males were evaluated for sperm parameters and reproductive tract histopathology following the breeding period. Females were exposed throughout gestation and lactation. Dams and pups were necropsied at weaning. Decreases in serum T3 and T4 were observed on Postnatal Days 21 and 40 in male and female pups exposed to 100 ppm chlorite or above. Additionally, groups of males were exposed to 0, 10, 100, or 500 ppm ad libitum in the drinking water to confirm observed subtle reproductive effects and examine dose-effect relationships. A significant increase in the percentage of abnormal sperm morphology (P less than 0.001) and decrease in sperm direct progressive movement (P less than 0.01) were observed for adult males at chlorite levels of 100 or 500 ppm. Since other clinical and reproductive endpoints were not affected, sperm morphology and sperm direct progressive movement may be two of the more sensitive indicators of reproductive damage.

Animals↗
PubMed1986

Dominant lethal effects of subchronic acrylamide administration in the male Long-Evans rat.

Acrylamide, a widely used vinyl monomer, is well known as a neurotoxin but inactive as a mutagen in bacterial test systems. The experiments reported demonstrate that after subchronic oral dosing in the male rat, acrylamide induced significant elevations in both pre- and post-implantation loss following dominant lethal testing. These effects were seen at doses which failed to produce clinical or pathological evidence of neurotoxicity. In an accompanying cytogenetic study, no increase in chromosome aberrations was observed in spermatogonia or spermatocytes of treated animals. When spermatocytes from treated spermatogonial stem cells were analyzed, reciprocal translocations (4) were observed in the treated animals and not in the control, but the significance of this result still needs to be established.

Acrylamide↗
PubMed1986

Evaluation of the reproductive toxicology of 2,4,6-trichlorophenol in male and female rats.

The toxicity of chlorinated organic compounds which may be generated as a by-product of drinking water chlorination has been an issue of increasing concern. Relatively few data are available concerning their reproductive toxicity. The present study was designed to evaluate the reproductive effects of one of these compounds, 2,4,6-trichlorophenol (TCP), in male and female rats. Adult males were treated with either 0, 100, 500, or 1000 mg/kg of TCP (po) for 10 weeks, at which time semen evaluations were conducted on ejaculates recovered from the genital tract of receptive females. Fertility was assessed in the 0- and 1000-mg/kg groups. Females were treated with identical doses for 2 weeks prior to pregnancy then throughout gestation. Dams were allowed to litter and pup development was monitored until Day 42 postpartum. TCP had no effect on any sperm parameter or male fertility. Treatment of females with 1000 mg/kg of TCP produced gross maternal toxicity as reflected in increased lethality and decreased weight gains in the dams. However, no treatment-related differences were seen in litter sizes or pup survival. Male and female birth weights were significantly depressed in the 500- and 1000-mg/kg groups; these differences disappeared by Day 4 postpartum, suggesting that they were a reflection of maternal toxicity. To this extent, the reproductive processes of male and female rats do not appear to be a primary target for the effects of TCP.

Animals↗
PubMed1986

Reproductive toxicity associated with acrylamide treatment in male and female rats.

The present study was designed to evaluate the influence of acrylamide (ACR) on male and female reproductive function. Male rats received ACR in drinking water (50, 100, or 200 ppm) for up to 10 wk. Copulatory behavior, semen, and (for controls and 100 ppm only) fertility and fetal outcomes were evaluated. Females received ACR (25, 50, 100 ppm) for 2 wk prior to initiation of breeding and then throughout gestation and lactation. Hindlimb splaying was apparent in the 200-ppm males by wk 4; less severe splaying appeared in the 100-ppm group at wk 8. Disruptions in copulatory behavior preceded the appearance of this ataxia. These disruptions in mating performance interfered with ejaculatory processes and subsequent transport of sperm, since semen was found in the uterus of only 1 of the 15 females mated with the 100-ppm males at wk 9. Moreover, only 33% of the females mated (wk 10) to the 100-ppm males were pregnant. Postimplantation loss was also significantly increased in this group. Hindlimb splaying appeared in the females receiving 100 ppm ACR during wk 1-2 of pregnancy. Body weight and fluid intake were also depressed. Dams in the 50-ppm group showed depression in these parameters during the last 2 wk of lactation. ACR did not significantly affect mating performance of the females, pregnancy rates, litter size, or survival. However, ACR did significantly depress pup body weight at birth (100-ppm group) and weight gain during lactation through post-weaning, d 42 (50- and 100-ppm groups). Vaginal patency was delayed in the 100-ppm group only.

Acrylamide↗
PubMed1986

Reproductive toxicology of disinfection by-products.

The chronic exposure of large segments of the population to disinfected drinking water has necessitated an evaluation of the health effects of the by-products of the chlorination process. This paper reviews the available information concerning the reproductive consequences associated with exposure to disinfection by-products. Four groups of compounds are discussed: the trihalomethanes, in particular chloroform; the chlorinated phenols; chlorinated humic substances; and the haloacetonitriles. In the pregnant female, chloroform and the 2- and 2,4-chlorophenols produced low levels of embryo- and fetotoxicity. Chloroform induced terata when administered by inhalation. The chlorinated humic substances and 2,4,6-trichlorophenol were without significant reproductive effects. The haloacetonitriles showed in utero toxicity, becoming more severe with increasing halogen substitution.

Acetonitriles↗
PubMed1986

Reproductive effects of alternative disinfectants.

Organohalides formed through the reaction of chlorine and organic compounds in natural and waste waters pose potential health hazards. For this reason, alternative water disinfectants that do not form organohalides are being investigated with great interest. Limited data are available on the health effects, in particular reproductive toxicity effects, of these compounds. In our laboratory, we have examined the reproductive effects of chloramine and chlorine administered by gavage in Long-Evans rats. Animals were treated for a total of 66 to 76 days. Males were treated for 56 days and females for 14 days prior to breeding and throughout the 10-day breeding period. Females were treated throughout gestation and lactation. Following breeding, the males were necropsied and evaluated for sperm parameters and reproductive tract histopathology. Adult females and some pups were necropsied at weaning on postnatal day 21. Other pups were treated postweaning until 28 or 40 days of age. These pups were evaluated for the day of vaginal patency and thyroid hormone levels. No differences were observed between control rats and those rats exposed to up to 5 mg/kg/day chlorine or 10 mg/kg/day chloramine when fertility, viability, litter size, day of eye opening, or day of vaginal patency were evaluated. No alterations in sperm count, sperm direct progressive movement (micron/sec), percent motility, or sperm morphology were observed among adult male rats. In addition, male and female reproductive organ weights were comparable to their respective control groups, and no significant histopathologic changes were observed among chlorine- or chloramine-treated male and female rats.

Animals↗
PubMed1985

Quality assurance audit: sodium-restricted menus.

A quality assurance audit was performed to evaluate the accuracy of prescribed sodium-restricted diets received by hospitalized patients. Sodium values were identified for all items on the audited sodium-restricted menu. Actual sodium values of the items to be served in a 24-hour period were tabulated from 48 menus after they had been corrected by the nutrition care clerk and compared with the prescribed sodium level. An acceptable variation of calculated sodium level vs. prescribed sodium level was determined to be plus or minus 10%. Of the sampled menus, 14.6% fell within this range, 22.9% were above, and 62.5% were below the standard set. Results of the audit led to training of clerks in calculation of sodium-restricted menus and inservice programs for all employees involved in patient foodservice regarding sodium-restricted diets. The results of a reaudit performed using the same methods showed a decrease to 12.2% of the menus above the standard and an increase to 26.8% in the number that met the standard, indicating increased accuracy of sodium-restricted diets.

Diet, Sodium-Restricted↗
PubMed1984

Effects of oral exposure to trichloroethylene on female reproductive function.

The present study was conducted to determine if subchronic oral exposure to trichloroethylene (TCE) influenced female reproductive performance, and if TCE or major metabolites trichloroacetic acid (TCA) and trichloroethanol (TCOH) preferentially accumulated in female reproductive organs or neonatal tissues. Female Long-Evans hooded rats were exposed to vehicle (corn-oil), 10, 100 or 1000 mg/kg/day by gavage for 2 weeks before mating and throughout mating to day 21 of pregnancy. Gas chromatography analysis of tissues from females at the end of premating exposure indicated that TCE levels were uniformly high in fat, adrenals and ovaries across treatment groups, while uterine tissue had relatively high levels of TCA. Female fertility, however, was not influenced in any treatment group. In the 1000 mg/kg/day group, 5 out of 23 females died and weight gain was significantly depressed throughout the treatment period. Neonatal survival was significantly depressed in this group alone, with the majority of deaths occurring among female offspring at the time of birth. TCA levels in blood, liver, and milk contents of the stomach in female but not male neonates increased across treatment groups. These results indicate that oral exposure to TCE at levels below those causing limiting maternal toxicity had no influence on pregnancy outcome, and that the accumulation of TCE and TCA in ovaries, adrenals and uteri had no influence on mating success.

Administration, Oral↗
PubMed1984

Zinc amelioration of cadmium-induced teratogenesis in vitro.

Mouse embryos were exposed to cadmium (5.35 micrograms/ml) for either 0.5h or 1h and then transferred to fresh serum for the duration of the experiment. Embryos exposed for 0.5h developed numerous malformations that were primarily localized to the craniofacial region. Embryos exposed for 1h to the same level of cadmium all failed to thrive. In a separate series of experiments zinc (10 micrograms/ml) was added 15 minutes prior to the addition of cadmium. Embryos treated with cadmium for 30 min. after the addition of zinc, resulted in 15 of 16 embryos developing normally. The second group of embryos treated for 1h after preincubation with zinc resulted in 93% of the embryos surviving after 48h, albeit malformed. These results suggest that: 1) Exposure time to a teratogen is a critical parameter to consider when designing in vitro experiments 2) zinc is effective in protecting embryos against cadmium induced teratogenesis and 3) the whole embryo culture system is effective in demonstrating biological interactions between agents.

Abnormalities, Drug-Induced↗