Gestational mercury vapor exposure and diet contribute to mercury accumulation in neonatal rats.

Exposure of pregnant Long-Evans rats to elemental mercury (Hg0) vapor resulted in a significant accumulation of Hg in tissues of neonates. Because elevated Hg in neonatal tissues may adversely affect growth and development, we were interested in how rapidly Hg was eliminated from neonatal tissues. Pregnant rats were exposed to 1, 2, or 4 mg Hg0 vapor/m3 or air (controls) for 2 hr/day from gestation day 6 (GD6) through GD15.

Evaluation of sensory evoked potentials in Long Evans rats gestationally exposed to mercury (Hg0) vapor.

Mercury is known to alter neuronal function and has been shown to cross the placental barrier. These experiments were undertaken to examine if gestational exposure to mercury vapor (Hg(0)) would result in alterations in sensory neuronal function in adult offspring. Dams were exposed to 0 or 4 mg/m(3) Hg(0) for 2 h/day from gestational days 6-15.

Concordance across species in the reproductive and developmental toxicity of tetrachloroethylene.

Reproductive and developmental toxicities resulting from exposure to tetrachloroethylene include delayed or impaired conception, sperm quality, death during development, developmental neurotoxicity, and growth retardation. In most cases there was concordance between rodents and humans. The risk assessments indicated that neurotoxicity was the most sensitive endpoint for inhalation, whereas growth retardation was the most sensitive endpoint when exposure was by the oral route.

Genomic analysis of the rat lung following elemental mercury vapor exposure.

Elemental mercury (Hg0) is a highly toxic chemical with increasing public health concern. Although the lung receives the highest exposure to Hg0 vapor, it is resistant to Hg0 toxicity relative to the kidney and brain. In an earlier study, exposure of rats to 4 mg Hg0 vapor/m3, 2 h per day for 10 days, did not produce pathological alterations in the lung but increased metallothionein and glutathione S-transferase in the kidney.

Effect of mercury vapor exposure on metallothionein and glutathione s-transferase gene expression in the kidney of nonpregnant, pregnant, and neonatal rats.

Elemental mercury (Hg(0)) is a ubiquitous toxic pollutant. Exposure to Hg(0) vapor typically is by inhalation, and the kidney is the primary target organ. Glutathione (GSH) and metallothionein (MT) appear to mitigate mercury toxicity.

Three-generation reproduction study of rats receiving acrylonitrile in drinking water.

Acrylonitrile, a high volume organic chemical, was tested for reproductive effects in a three generation drinking water study with two matings per generation. Sprague-Dawley rats were exposed to acrylonitrile in drinking water at 0, 100, or 500 ppm. This corresponds to 0, 11+/-5 and 37+/-10 mg/kg, respectively, for males and 0, 20+/-3 and 40+/-8 mg/kg per day for the females, respectively.

Disposition of inhaled mercury vapor in pregnant rats: maternal toxicity and effects on developmental outcome.

The disposition and toxicity of inhaled elemental mercury (Hg0) vapor for pregnant Long-Evans rats, and potential adverse effects on reproductive outcome were investigated. Rats were exposed to 0, 1, 2, 4, or 8 mg Hg0/m(3) for 2 h/day from gestation day (GD) 6 through GD 15. Maternal toxicity occurred primarily in rats exposed to 4 and 8 mg/m(3) and was manifested as a concentration-related decrease in body weight gain and mild nephrotoxicity.

Valproate-induced limb malformations in mice associated with reduction of intracellular pH.

Valproic acid (VPA) is a commonly used antiepileptic agent that recently has been found useful in the treatment of affective disorders and prophylaxis of migraine. VPA induces congenital malformations, especially spina bifida, in the offspring of women treated with this agent during early pregnancy. The mechanism by which VPA induces abnormal development remains unknown despite many studies in experimental animals in which VPA causes malformations similar to those seen in human infants.

Physiologically based pharmacokinetics of methoxyacetic acid: dose-effect considerations in C57BL/6 mice.

Methoxyacetic acid (MAA), a weak acid with a pKa of 3.57, was used to test the broad hypothesis that distribution of weak acids in maternal and fetal tissues is determined principally by the pKa of the acid and the pH values of tissue and fluid compartments and to examine tissue dose-teratogenesis relationships, as well as administered dose-teratogenesis relationships. Five related experimental studies were conducted in pregnant C57BL/6CrIBR mice: a conventional dose-response study of developmental toxicity and transplacental pharmacokinetics in mice, a second dose-response study in which reproductive outcomes in litters from individual dams were related to individual pharmacokinetic behavior, a protein-binding experiment, an embryo tissue localization study, and determination of pH in maternal and embryonic compartments after exposure to MAA.

A physiologically based pharmacokinetic model for fluoride uptake by bone.

A sex-specific, physiologically based pharmacokinetic (pbpk) model has been developed to describe the absorption, distribution, and elimination of fluorides in rats and humans. Growth curves generated by plotting mean body weights (kg) against age (weeks or years) are included in the simulation model to allow the integration of chronic fluoride exposure from birth to old age. The model incorporates age and body weight dependence of the physiological processes that control the uptake of fluoride by bone and the elimination of fluoride by the kidneys.

A physiologically based kinetic model of rat and mouse gestation: disposition of a weak acid.

A physiologically based toxicokinetic model of gestation in the rat and mouse has been developed. The model is superimposed on the normal growth curve for nonpregnant females. It describes the entire gestation period including the period of organogenesis.

Consideration of the target organ toxicity of trichloroethylene in terms of metabolite toxicity and pharmacokinetics.

Trichloroethylene (TRI) is readily absorbed into the body through the lungs and gastrointestinal mucosa. Exposure to TRI can occur from contamination of air, water, and food; and this contamination may be sufficient to produce adverse effects in the exposed populations. Elimination of TRI involves two major processes: pulmonary excretion of unchanged TRI and relatively rapid hepatic biotransformation to urinary metabolites.

Pharmacokinetically based risk assessment of workplace exposure to benzene.

Cancer risk from exposure to benzene for a working lifetime was estimated from data obtained in studies with rodents. Cancers of the Zymbal gland and the blood-forming system were selected as endpoints for the assessment because of their consistent occurrence. The combined metabolites were judged from toxicological data to be the best representative of the reactive agent.

Dose paradigms for inhaled vapors of primary carcinogens and their impact on risk assessment.

In the assessment of risk, several factors affect predictions: selection of reactive agent, selection of tumor incidence data, modeling of dose, scaling across species, adjustment for differences in duration and frequency of exposure, and selection of the most suitable risk extrapolation model. If the endpoints, exposure regimen, and the model for risk extrapolation are constant, then the review of dose paradigms will illustrate the effect of dose modeling on risk, since by definition the reactive agent is the primary carcinogen. The response incidence in lifetime inhalation bioassays of two primary carcinogens, ethylene oxide and formaldehyde, was used with different dose paradigms to estimate risk from maximum lifetime occupational exposures.

Risk assessment and oncodynamics of ethylene oxide as related to occupational exposure.

Two rat inhalation bioassays have been integrated into the risk assessment on the carcinogenicity of ethylene oxide (EO). The carcinogenic findings as well as relevant metabolism and pharmacokinetic data are reviewed. Brain tumors were selected as the endpoint for the assessment of risk because of the indication that adverse effects on the nervous system, related to EO exposure, were consistent across species.

Biological basis for extrapolation across mammalian species.

The rationale for extrapolation or "scaling" across species is founded in the commonality of anatomic characteristics and the universality of physiologic functions and biochemical reactions. The development of the allometric equation, Y = aWn, relating species body size (W) with various morphological, physiological, biochemical, pharmacological, and toxicological characteristics, as the fundamental basis for extrapolation of biological data from laboratory animals to man is outlined. The familiar methods of extrapolation on the basis of "milligrams per kilogram body weight" and "body surface area" are simply examples, W1.

Chronic toxicity and three-generation reproduction study of styrene monomer in the drinking water of rats.

Chronic toxicity and reproductive performance were evaluated in groups of rats receiving styrene monomer in their drinking water at nominal concentrations of 0, 125, or 250 ppm. Fifty male and 70 female rats in each test group and 76 males and 104 females in the control group were placed on a 2-year study and followed for observations of general health which included measurement of body weight, food and water consumption, hemograms, clinical chemistries, urinalysis, and histopathological examination. Ten males and 20 females from each group in the study were mated to produce F1 pups.

Teratology and reproduction studies with triclopyr in the rat and rabbit.

Triclopyr (3,5,6-trichloro-2-pyridyloxyacetic acid), being developed as a new herbicide for use on brush and weeds, was evaluated for its potential effects on reproduction, and embryonal and fetal development. Pregnant Sprague-Dawley rats were given doses of 0, 50, 100, or 200 mg/kg/day by gavage on Days 6 through 15 of gestation. Dose-related signs of maternal toxicity were observed during the treatment period.

Testing of selected workplace chemicals for teratogenic potential.

The reproductive toxicity and teratogenic potential of 19 industrial chemicals have been investigated during the past 3 a. Preliminary studies utilizing intraperitoneal treatments of rats on days 1-15 of gestation have been conducted on the following ten chemicals: allyl chloride, bisphenol A, copper naphthenate, ethylene dibromide, hexachlorobutadiene, 2-mercaptobenzothiazole, methyl styrene, naphthalene, 2-nitropropane, and 1,2,3-trichloropropane. Studies utilizing inhalation exposure of rats and rabbits on days 1-19 and 1-24, respectively, of gestation have been conducted on the following nine chemicals: butylene oxide, carbon disulfide, 2-ethoxyethanol, ethyl benzene, methyl bromide, nitrous oxide, styrene oxide, tetrachloroethylene, and trichloroethylene.

Teratology study in mice subjected to inhalation of diethylhydroxylamine, nitroethane, and diethylamine hydrogen sulfite.

Pregnant female mice were exposed from Days 6 to 17 of pregnancy to 8.9 +/- 2.0 ppm of diethylhydroxylamine and 14.

The effect of massive transplacental iron loading.

Intravenous injection of three doses of 50 mg Fe/kg (total dose 150 mg Fe/kg) as iron dextran into rabbits late in pregnancy (days 26, 28, and 30 of gestation) reduced the weight gain of the dams and increased fetal mortality. Three doses of 20 mg Fe/kg also increased fetal mortality, while three doses of 5 mg Fe/kg were without effect. Liver and kidney iron concentrations of the dams and offspring were markedly increased at the time of parturition by treatment with a total dose of 150 mg Fe/kg.