Overview of reproductive and developmental toxicity studies of 1,3-butadiene in rodents.

A series of studies to further evaluate the developmental and reproductive toxicity of inhaled 1,3-butadiene was sponsored by the National Toxicology Program. Pregnant Sprague-Dawley rats (24-28/group) and Swiss (CD-1) mice (18-22/group) were exposed to atmospheric concentrations of 0, 40, 200, or 1000 ppm 1,3-butadiene for 6 hr/day on days 6 through 15 of gestation (dg) and killed on dg 18 (mice) or dg 20 (rats). Subsequently, the uterine contents were evaluated; individual fetal body weights were recorded; and external, visceral, and skeletal examinations were performed. In rats, maternal toxicity was observed in the 1000-ppm group in the form of reduced extragestational weight gain and, during the first week of treatment, decreased body weight gain. Under these conditions, there was no evidence of developmental toxicity in rats. In contrast, results of the mouse developmental toxicity study indicated that the fetus may be more susceptible than the dam to inhaled 1,3-butadiene. Maternal toxicity was observed in mice at the 200- and 1000-ppm 1,3-butadiene exposure levels, whereas 40 ppm and higher concentrations of 1,3-butadiene caused significant exposure-related reductions in the mean body weights of male fetuses. Mean body weights of female fetuses were also reduced at the 200- and 1000-ppm exposure levels. No increased incidence of malformations was observed in either study. Other studies addressing male reproductive and mutagenesis end points were performed with B6C3F1 mice (sperm-head morphology) and Swiss (CD-1) mice (dominant lethal study).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of diltiazem in patients with unstable angina pectoris.

The pharmacokinetics of diltiazem and its major metabolites, deacetyldiltiazem and N-monodemethyl-diltiazem, were studied after single and chronic oral administration in eight patients aged 45 to 69 years with unstable angina pectoris, treated by diltiazem, 120 mg t.i.d. After a single oral dose the time to peak plasma diltiazem concentration was 3.4 (2.1 to 5.0) hours and the elimination half-life was 6.6 hours (4.4 to 10.8 hours). These were unchanged after repeated oral administration (16 to 19 doses). The mean trough (8 hours after administration) plasma diltiazem level after six consecutive doses was 167 micrograms/L (63 to 286 micrograms/L) and was thereafter stable. With chronic administration the AUC increased by a factor of 2.24 +/- 0.31 (SEM; P less than 0.01). Plasma protein binding of diltiazem in these patients ranged from 83% to 93% whereas deacetyldiltiazem binding ranged from 58% to 75%. Plasma protein binding was independent of drug concentration and duration of treatment. Thus an average dose of 120 mg diltiazem given every 8 hours would appear to be a suitable regimen of treatment in most patients with angina pectoris, although users should be aware that there is a significant interpatient variability in steady-state diltiazem concentrations and that a significant accumulation of diltiazem occurs with chronic therapy.

Lung development and postnatal survival for rats exposed in utero to a high-boiling coal liquid.

Previous studies performed in this laboratory indicated that exposure of rat fetuses to high-boiling coal liquids from 12-14 days of gestation (dg) induced a number of major malformations, including cleft palate, diaphragmatic hernia and small lungs. The study reported here was designed to determine postnatal viability and development of survivors following in utero exposure to Harmarville process solvent (HPS), a wide-boiling-range (150 to greater than 455 degrees C) coal liquid. For this study, 0.74 g kg-1 of the coal liquid was administered (by intragastric intubation) to rats from 12 to 14 dg. Offspring were evaluated for postnatal survival, growth and lung and thymus weights. Randomly selected pups from control and treated litters were killed and necropsied at 1, 3, 7 and 21 days postpartum. In addition, data for control pups were obtained at 0.25 and 0.5 days postpartum for comparison with body, lung and thymus weights of pups that died during this interval. Fifty-four per cent of the exposed pups and 9% of the control pups died between birth and 3 days postpartum. Of the treated pups that died, 10% (6/5; pups/litters) had cleft palate, 27% (17/9) had small lungs and 33% (21/8) had both cleft palate and small lungs. No gross malformations were observed in the remaining 30% of the dead pups. Microscopic examination of lungs from HPS-treated pups revealed no evident histological abnormalities. Body, lung and thymus weights for treated animals that died were significantly less than those of controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Developmental toxicity following oral administration of a high-boiling coal liquid to pregnant rats.

Heavy distillate (HD), the highest-boiling coal liquid from the solvent-refined coal-II process (SRC-II), was administered by intragastric (IG) intubation to pregnant rats. Five dose levels of HD (0.09, 0.14, 0.18, 0.36 and 0.74 g kg-1), were given daily from 12 to 16 days of gestation and the rats were killed at 20 days of gestation. Maternal body weights and weights of the liver, kidneys, spleen, adrenals, thymus, ovaries and the gravid uterus were obtained. Gravid uteri were evaluated for prenatal mortality. Live fetuses were examined for malformations and weighed; fetal lungs were excised and weighed. Maternal (extragestational) weight gains and thymic weights diminished in all groups that received the SRC material. Adrenal weights were increased in all treated animals, except for those in the lowest-dose group (0.9 g kg-1). There was significant maternal mortality at 0.74 g kg-1 and increased intrauterine mortality at doses of 0.37 and 0.74 g kg-1. Placental weight was depressed, and the incidence of fetal anomalies was increased at 0.14 g kg-1 and all higher dose levels.

Availability of toxic trace metals to the conceptus.

Energy production releases numerous toxic metals into the environment. Among those metals which have been shown to be toxic to the conceptus are cadmium, lead, mercury, plutonium and vanadium. This paper reviews the results from the authors' studies of pregnant rats exposed to these metals by parenteral administration, inhalation or gastric intubation. In addition, direct measurements were made of maternal blood flow and clearance of metals across the guinea pig placenta to serve as conceptual examples of factors which regulate the effects of the metals on the fetus. Discussion includes the influence of route of maternal exposure and subsequent absorption, gestational age at exposure, metal behavior in the maternal bloodstream, movement of metals across the placenta, and distribution of metals in the products of conception.

Reproductive-toxicologic assessment of the epoxides ethylene oxide, propylene oxide, butylene oxide, and styrene oxide.

Ethylene oxide (CAS no 75-21-8), propylene oxide (CAS no 75-56-9), butylene oxide (CAS no 106-88-7), and styrene oxide (CAS no 96-09-3) were tested for teratogenic activity by inhalation exposure of rats and rabbits. Ethylene oxide and propylene oxide were tested at only one concentration in both species (150 ppm for ethylene oxide and 500 ppm for propylene oxide). Butylene oxide was tested at 250 and 1,000 ppm in both species, while styrene oxide was tested at 100 ppm in rats and 15 and 50 ppm in rabbits. For each of these four epoxides, the acute toxicity was similar for pregnant and nonpregnant rats. Styrene oxide was the most toxic in both species, and rabbits were more sensitive than rats. Rats exposed to propylene oxide for 7 h/d, 5 d/week for three weeks before breeding had a significant reduction in the number of corpora lutea. Fetal mortality was not increased, but significantly fewer mated rats were found pregnant following gestational exposure to styrene oxide, a finding suggesting preimplantation loss. In rabbits exposed to styrene oxide, the number of resorptions per litter was increased in concentration related manner, but differences were not statistically significant. Fetal examination revealed evidence of fetotoxicity with all four epoxides. There was no overt teratogenic activity, but a number of minor morphologic aberrations were detected.

Effect of dose level and pregnancy on the distribution and toxicity of intravenous lead in rats.

Female Wistar rats were injected intravenously with tracer levels of 210Pb, alone or combined with carrier Pb(NO3)2 at 5 or 25 mg/kg body weight at 9 or 15 days of gestation (dg). Tissue 210Pb distribution and retention, and lead excretion, were measured several times during the first 30 h and at 20 dg. Toxic effects following the administration of 25 mg/kg (a teratogenic dose) included an early decrease in hematocrit, hematuria, gastrointestinal hemorrhage, and diarrhea, as well as an eventual loss of body weight and an increase in spleen and kidney weights. The stage of pregnancy at injection did not affect the retention and distribution of lead in major organs other than the reproductive system. Following injection of the 25-mg/kg dose, deposition of lead in the liver, kidney, spleen, and lung was elevated. Disproportionately high plasma lead levels were also observed at early times after the injection of the 25-mg/kg dose, and may act as a significant factor in placental lead transfer and subsequent malformations or fetal mortality.

Distribution and effects of intravenous lead in the fetoplacental unit of the rat.

Lead metabolism was studied in the fetoplacental unit (FPU) of Wistar rats during the genesis of developmental abnormalities and embryonic death. Female rats were injected iv with tracer 210Pb(NO3)2, alone or in combination with 5 or 25 mg Pb(NO3)2/kg, at 9 or 15 days of gestation (dg). The distribution of lead and its effects were determined in the FPUs during the ensuing 30-h period and at 20 dg. Hemorrhage of the egg cylinder was noted as early as 6 h postinjection of 25 mg/kg at 9 dg. By 20 dg, fetuses exhibited characteristic stunting and external malformations (gastroschisis and severe skeletal defects). Administration of this dose at 15 dg produced petechial hemorrhage in fetal brain within 90 min; more massive hemorrhage was a consistent observation by 24 h. At 20 dg, embryo mortality was 44% in rats injected with 25 mg/kg at 9 dg and 100% in those injected at 15 dg. At 90 min after injection, lead content of 15-dg FPUs was 10 times that of the 9-dg FPUs, but the weights of the 15-dg FPUs were 16 times greater. Values remained relatively constant in 15-dg FPUs for 30 h, but early clearance was observed after injection at 9 dg, with a return to 90-min values by 20 dg. In the 15-dg FPUs, placental clearance was followed by fetal lead incorporation, which reached a maximum at 6 h. Fetal lead values were constant from 6 to 30 h after injection at tracer and 5-mg/kg dose levels, but values increased progressively at 25 mg/kg. Both temporal and quantitative relationships of fetal lead metabolism were disrupted by the 25-mg/kg dose, but the nature of the effect was determined by the stage of fetal development at exposure.

Acute myelomonocytic leukemia manifested as myelophthisic anemia in a dog.

A 10-year-old, Golden Retriever-type castrated male dog was found to have a hemogram consistent with myelophthisic anemia. Within 30 days the hemogram changed in such a manner that a myeloproliferative disorder was evident. On the basis of hematologic, cytochemical, and cytologic findings, acute myelomonocytic leukemia was diagnosed.

Bone tumors induced by inhalation of 238PuO2 in dogs.

Plutonium-238, an alpha-emitting radionuclide, is used as a heat source in thermoeleltric power generators such as have been employed on lunar expeditions of communications satellites and in cardiac pacemakers. It has an 86.4 year half-life and emits 5.5 MeV alpha particles. Beagle dogs were given single 10-30 minute exposures to 238PuO2 aerosols to study the long-term translocation of plutonium and biological effects. Dogs with a terminal body burden ranging from 7-260 muCi were euthanized due to respiratory insufficiency related to plutonium-induced pneumonitis during the first 3 years after exposure. Nine of the 11 dogs euthanized during the 4-6 year postexposure period had osteosarcomas. The terminal plutonium body burden in the tumor-bearing dogs ranged from 0.5-2.6 muCi with 30-55% of the plutonium in the skeleton. Experiments are in progress to further define the dose-effect relationship of inhaled 238PuO2 and investigate the mechanisms of plutonium-induced neoplasia.

Studies of duplex (copper-coated) wires for use in intrauterine devices.

PIP: An investigation to develop and study duplex wire for use in IUDs was initiated by the observation that copper wires wound on IUDs occasionally fragmented after prolonged in vivo use. The duplex wires consist of an exposed active copper surface plated onto an inert inner core to maintain structural continuity. Data demonstrated that the dissolution rates as well as surface changes and biological effects are independent of whether stainless steel, Inconnel or Tophet-M was used as the core. Small IUDs can be wound with a duplex wire in a manner identical to that presently used with pure copper to resist fragmentation and to provide contraceptive effects.^ieng

Uterine copper distribution in monkeys implanted with copper-carrying intrauterine devices.

Chemical and histochemical analyses were carried out on uteri of four monkeys in which plastic IUDs or Cu-IUDs had been implanted for 36 to 43 days. The mean uterine copper content of the plastic-treated animals was 1.1 mug/gm (mean of two), while this value for the Cu-IUD treated monkeys was 1.7 mug/gm. The copper was distributed primarily in the cyclically renewed regions of the endometrium: the luminal fluid, endometrial surface, and superficial lamina propria. The element was localized and was not uniformly distributed in these regions. Copper analyses of plasma, liver, and kidney showed no differences between these two groups. Histopathologic evaluation revealed some areas of edema and increased numbers of neutrophils in plastic-IUD-treated animals. In the Cu-IUD-implanted monkeys, similar changes were observed as was a flattening of the surface epithelium. The endometrium had a loose areolar appearance. The copper elution rate was about 90 mug/day, about twice that observed in women using Cu-IUDs.

Strontium-90: effects of chronic ingestion on farrowing performance of miniature swine.

In experiments involving the ingestion of strontium-90 by nearly 800 female miniature swine and extending over three generations, no significant differences in litter size, percentage of stillborn, or birth weight were observed between controls and animals ingesting up to 625 microcuries of strontium-90 per day. At 625 microcuries per day, these animals were ingesting more than a million times the peak value of strontium-90 ever reported in the American diet. Animals on 3100 microcuries per day did not survive the gestation period. From these studies, it is evident that feeding levels of strontium-90 high enough to affect fetal or neonatal mortality in this species will not permit maternal survival long enough for the bearing of young.