Developmental toxicity of four glycol ethers applied cutaneously to rats.

Previous NIOSH studies demonstrated the embryo- and fetotoxicity and teratogenicity of ethylene glycol monoethyl ether (EGEE) applied to the shaved skin of pregnant rats. In the present study ethylene glycol monoethyl ether acetate (EGEEA), ethylene glycol monobutyl ether (EGBE), and diethylene glycol monoethyl ether (diEGEE) were tested in the same experimental model, using distilled water as the negative control and EGEE as a positive control. Water or undiluted glycols were applied four times daily on days 7 to 16 of gestation to the shaved interscapular skin with an automatic pipetter. Volumes of EGEE (0.25 mL), EGEEA (0.35 mL), and diEGEE (0.35 mL) were approximately equimolar (2.6 mmole per treatment). EGBE at 0.35 mL four times daily (approximately 2.7 mmole per treatment) killed 10 of 11 treated rats, and was subsequently tested at 0.12 mL (0.9 mmole) per treatment. EGEE- and EGEEA-treated rats showed a reduction in body weight relative to water controls that was associated with completely resorbed litters and significantly fewer live fetuses per litter. Fetal body weights were also significantly reduced in those groups. Visceral malformations and skeletal variations were significantly increased in EGEE and EGEEA groups over the negative control group. No embryotoxic, fetotoxic, or teratogenic effects were detected in the EGBE- or diEGEE-treated litters.

Systolic time intervals in chronic hypertension: Alterations and response to treatment.

Systolic time interval studies were performed to evaluate left ventricular performance in 28 patients with untreated systemic hypertension but without clinical heart failure. The pre-ejection period (PEP) was significantly prolonged (p smaller than 0.001) and left ventricular ejectime time (LVET) was shortened (p smaller than 0.02) when compared to rate-corrected predicted values. The PEP/LVET ratio was abnormally high in 18 of the patients and the average ratio was 0.45 ( smaller than 0.001). Eleven patients with abnormal time intervals were restudied during treatment with antilypertensive drugs. The PEP/LVET raio decreased in ten and became normal in nine. The average ratio decreased from 0.49 to 0.41 (p smaller than 0.001), due to both shortening of PEP (p smaller than 0.02) and lengthening of LVET (p smaller than 0.001). These findings indicate that alterations in left ventricular function may occur commonly in chronic hypertension in the absence of clinical heart failure, and can be reversed with appropriate therapy. This technique may be useful in evaluating hypertensive patients and in determining the efficacy of treatment.

Interlaboratory studies with the Chinese hamster V79 cell metabolic cooperation assay to detect tumor-promoting agents.

Three laboratories participated in an interlaboratory study to evaluate the usefulness of the Chinese hamster V79 cell metabolic cooperation assay to predict the tumor-promoting activity of selected chemicals. Twenty-three chemicals of different chemical structures (phorbol esters, barbiturates, phenols, artificial sweeteners, alkanes, and peroxides) were chosen for testing based on in vivo promotion activities, as reported in the literature. Assay protocols and materials were standardized, and the chemicals were coded to facilitate unbiased evaluation. A chemical was tested only once in each laboratory, with one of the three laboratories testing only 15 out of 23 chemicals. Dunnett's test was used for statistical analysis, and differences between treated- and control-cell responses were analyzed at P less than or equal to .01. Chemicals were scored as positive (at least two concentration levels statistically different than control), equivocal (only one concentration statistically different), or negative. For 15 chemicals tested in all three laboratories, there was complete agreement among the laboratories for nine chemicals. For the 23 chemicals tested in only two laboratories, there was agreement on 16 chemicals. With the exception of the peroxides and alkanes, the metabolic cooperation data were in general agreement with in vivo data. However, an overall evaluation of the V79 cell system for predicting in vivo promotion activity was difficult because of the organ specificity of certain chemicals and/or the limited number of adequately tested nonpromoting chemicals.

Effects on the peripheral nervous system of workers' exposure to carbon disulfide.

An evaluation of the effects of occupational exposure to carbon disulfide was performed in a sample of 156 male viscose rayon workers. A composite group of 233 workers drawn from two other artificial fiber plants located on the same premises as the rayon plant was used for comparison. Effects of CS2 on the peripheral nervous system (PNS) were evaluated in ulnar and peroneal nerves using measurements of maximum motor nerve conduction velocity (MCV) and distal latency; and sensory conduction velocity (SCV) in the sural nerve. Self-reported symptoms related to PNS disorders were also obtained from each study participant. Industrial hygiene records showed the rayon workers to have had CS2 exposures that generally had not exceeded 20 ppm. The overall mean number of years of CS2 exposure was 12.1 years (+/- 6.9 S.D.). The viscose rayon workers were divided prior to the study into three groups according to historical mean CS2 levels calculated for job titles, and area and personal CS2 samples were obtained during the conduct of the study to characterize each job. For these three groups the median CS2 levels were measured to be 1.0, 4.1 and 7.6 ppm. The comparison group's median CS2 level approximated 0.2 ppm. Results showed CS2-exposed workers to have small but statistically significant (p less than .05) reductions in sural SCV and peroneal MCV. Other neurophysiological measures consisting of distal latency, residual latency, and muscle or nerve action potential amplitudes showed no significant differences between study groups. A reduction in the ratio of amplitudes of muscle action potentials obtained from peroneal nerve stimulation was significant (p less than .05). Reductions in the peroneal nerve MCV were found to be related, in a dose response sense, to workers' cumulative exposure to CS2. No increase attributable to CS2 was found in the prevalence of symptoms related to PNS disorders. The results from this study generally agree with similar findings from Finland, Sweden and Italy, but at CS2 exposure levels lower than those previously reported for occupational exposure.

Behavioral and neurochemical alterations in the offspring of rats after maternal or paternal inhalation exposure to the industrial solvent 2-methoxyethanol.

The industrial solvent 2-methoxyethanol (2ME) has antifertility effects in male rats at 300 ppm and is teratogenic in rats and rabbits at 50 ppm. The present research investigated if exposure of paternal or maternal animals to 25 ppm 2ME, the current U.S. permissible occupational exposure limit, would produce detectable effects in the offspring. Eighteen male young-adult Sprague-Dawley rats were exposed to 25 ppm 2ME 7 hr/day, 7 days/week for 6 weeks; they were then mated with untreated females which were allowed to deliver and rear their young. In addition, groups of 15 pregnant rats were exposed 7 hr/day on gestation days 7-13 or 14-20 and allowed to deliver and rear their young. At birth, litters were culled to 4 females and 4 males for behavioral testing of neuromotor function, activity, and simple learning ability on days 10 through 90. In addition, brains from newborn and 21-day-old offspring were analyzed for neurochemical deviations from controls. No effects on paternal or maternal animals, nor on the number or weight of live offspring, were noted. Behavioral testing revealed significant differences from controls only in avoidance conditioning of offspring of mothers exposed on days 7-13. In contrast, neurochemical deviations were observed in brains from 21-day-old offspring from the paternally exposed group as well as from both maternally exposed groups; changes were numerous in the brainstem and cerebrum but were fewer in the cerebellum and midbrain. Thus it appears that both paternal and maternal inhalation of 25 ppm 2ME produces some effect which is reflected in neurochemical deviations in the offspring.

Methodology for selecting substances for the National Exposure Registry.

The National Exposure Registry was created in response to the pervasiveness of chemical contamination at the nation's waste sites and the relative lack of information on human health outcomes associated with long-term, low-level exposure to most of these substances. A ranking scheme was developed by the Agency for Toxic Substances and Disease Registry (ATSDR) to select the substances for which substance-specific subregistries of the National Exposure Registry would be developed. This scheme uses a general decision analysis approach that incorporates the most relevant and up-to-date data available on the substances found at sites known to ATSDR. There are currently four general subregistries (volatile organic compounds, dioxins, heavy metals, and radioactive substances) made up of persons exposed to specific primary contaminants, as selected by means of this ranking scheme.

Neurochemical, but not behavioral, deviations in the offspring of rats following prenatal or paternal inhalation exposure to ethanol.

In addition to its widespread social use, ethanol is used extensively as an industrial solvent. Inhalation exposures to ethanol which produce narcosis in maternal rats are not teratogenic. The present study sought to extend the previous research by including offspring from paternal exposures, and testing for behavioral disorders in the offspring following maternal or paternal exposures. Groups of 18 male (approximately 450 g) and 15 female (200-300 g) Sprague-Dawley rats were exposed 7 hours/day for six weeks or throughout gestation to 16000, 10000, or 0 ppm ethanol by inhalation and then mated with untreated rats. Litters were culled to 4 males and 4 females, and were fostered within 16 hours after birth to untreated dams which had delivered their litters within 48 hours previously. Offspring from paternally or maternally exposed animals performed as well as controls on days 10-90 in tests of neuromotor coordination (ascent on a wire mesh screen, rotorod), activity levels (open field, modified-automated open field, and running wheel), and learning ability (avoidance conditioning and operant conditioning). In addition, brains of 10 21-day-old pups were analyzed for neurochemical differences from controls in concentrations of protein and the neurotransmitters acetylcholine, dopamine, norepinephrine, 5-hydroxytryptamine, substance P, Met-enkephalin, and beta-endorphin. Levels of acetylcholine, dopamine, substance P, and beta-endorphin were essentially unchanged in the offspring of rats exposed to ethanol. Complex, but significant changes in levels of norepinephrine occurred only in paternally exposed offspring. 5-Hydroxytryptamine levels were reduced in the cerebrum, and Met-enkephalin levels were increased in all brain regions of offspring from both maternally and paternally exposed rats.

Behavioral teratology investigation of 1-propanol administered by inhalation to rats.

Due to their structural similarity to ethanol, a human teratogen, and their widespread use in industry, a series of industrial alcohols are being investigated for developmental toxicity. This paper presents the results of exposures to 7000 ppm 1-propanol, which is minimally toxic to maternal animals and produces a low incidence of teratogenicity, and to 3500 ppm 1-propanol, which is not toxic to maternal rats and produces no teratogenicity. Propanol vapors or filtered air was administered for 7 hr/day to 15 pregnant Sprague-Dawley rats throughout gestation or to 18 male rats daily for 6 weeks. Tests of offspring were: a) ascent on a wire mesh screen b) rotorod, c) open field and optically monitored activity, d) running wheel, e) avoidance conditioning, and f) progressive fixed ratio schedule of reinforcement. Brains from 10 rats per group were dissected into cerebrum, cerebellum, brainstem, and midbrain, and were assayed for protein, acetylcholine, dopamine, norepinephrine, serotonin, beta-endorphin, Met-enkephalin, and substance P. Overall, the results indicate that exposure to high concentrations of 1-propanol can affect fertility in exposed males (only 2 of 17 produced litters), but there were no consistent effects seen in the behavioral or neurochemical tests measured. This lack of effects is surprising based on predictions from the structural similarity of 1-propanol to ethanol, and on long-standing observations that toxicity (to adult animals) increases with carbon chain length among the aliphatic alcohols.

Teratogenicity of n-propanol and isopropanol administered at high inhalation concentrations to rats.

As part of a teratological evaluation of several alcohols, 10,000, 7000 and 3500 ppm n-propanol or isopropanol were administered by inhalation to groups of 15 pregnant Sprague-Dawley rats for 7 hr/day on gestation days 1-19. The dams were killed on day 20. Half of the foetuses were examined for skeletal defects and the others for visceral defects using the Wilson technique. The highest concentration of n-propanol produced only minimal maternal toxicity, as indicated by observation and by measurement of weight gain and feed and water intake. In contrast, the same concentration of isopropanol produced narcosis in the dams, retarded body-weight gain and reduced the feed intake. At 7000 ppm isopropanol, body-weight gain was retarded but there were no other observable effects in the dams. Following exposure to 10,000 ppm of either alcohol, there were significant (P less than or equal to 0.05) increases in resorptions and decreases in foetal weights compared with the control groups. Foetal weights were also reduced significantly following exposure to 7000 ppm of either alcohol and to 3500 ppm isopropanol. Significantly more litters had malformations following exposure to 10,000 or 7000 ppm of either alcohol, but these effects were seen only in the presence of maternal toxicity. At 3500 ppm, no detectable teratogenic effects were produced by either solvent.

Health effects of environmental contaminant exposure: an intrafile comparison of the Trichloroethylene Subregistry.

The establishment of the National Exposure Registry represents the first major effort toward longitudinal surveillance of general populations exposed long-term to low levels of specific substances in the environment. The authors investigated the National Exposure Registry's Trichloroethylene Subregistry intrasubregistry differences with respect to health outcomes and the possible relationships with types and levels of chemical exposure. Investigators divided the 4041 living members of the Trichloroethylene Subregistry into 4 subgroups, by type(s) of exposures (chemicals) and duration and level of exposures. The authors compared the reporting rates for 25 health outcomes across subgroups. The authors used logistic regression, in which age, sex, education, smoking history, and occupational history were the covariates. Statistically significant increases in reporting rates were seen with (a) increased maximum trichloroethylene exposures for the outcome stroke, (b) increased cumulative chemical exposure for respiratory allergies, and (c) duration of exposure for hearing impairment. Consistently elevated reporting rates across the exposure subgroups were seen for hearing impairment, speech impairment, asthma and emphysema, respiratory allergies, and stroke. Reporting rates for urinary tract disorders were related only to cumulative chemical levels. The authors noted that there appeared to be a relationship between trichloroethylene and reporting rates for speech impairment, hearing impairment, and stroke and between volatile organic compounds and asthma and emphysema, respiratory allergies, and urinary tract disorders.

Environmental personal injury litigation as one source of response effects: findings from the National Exposure Registry.

The potential for error in survey responses obtained from people involved with environmental personal injury litigation was examined in a registry of persons exposed to the chemical trichloroethylene. Two subgroups were selected and compared: environmental personal injury plaintiffs and nonlitigants residing in the same community. Self-reported information on demographic characteristics revealed no statistically significant differences. Although plaintiffs reported higher rates of symptoms and health problems, only 2 of the 20 comparisons on health were statistically significant. The overall similarity between the two groups suggests that environmental personal injury plaintiffs may be no more likely than nonlitigants to provide inaccurate information in health surveys.

The National Exposure Registry: procedures for establishing a registry of persons environmentally exposed to hazardous substances.

The Agency for Toxic Substances and Disease Registry has, as mandated in Superfund legislation, established the National Exposure Registry (NER). The purpose of the NER is to assess and evaluate the potential relationship between adverse health effects and environmental exposure for an exposed population, particularly the relationship between chronic health effects and long-term, low-level chemical exposures. The NER's primary goal is to facilitate epidemiology research by establishing multiple data bases (subregistries) that contain demographic, environmental, and health information on large populations exposed to selected chemicals. The Registry data mainly serve the purpose of being hypothesis-generating rather than hypothesis-testing. The NER is currently composed of subregistries of: (1) persons exposed to volatile organic compounds (VOCs)--a subset of registrants in whom trichloroethylene (TCE) is the primary VOC exposure, but others are present (N = 4,832), a subset in whom benzene is the primary VOC exposure (N = 1,142), and a subset in whom trichloroethane (TCA) and TCE are the highest VOC exposures (N = 3,666); and (2) persons with dioxin exposure (N = 250). Chromium and radioactive substances subregistries are planned.

Trichloroethylene--a review of the literature from a health effects perspective.

This report reviews the literature on the impact of exposure to trichloroethylene (TCE) on human health. Special emphasis is given to the health effects reported in excess of national norms by participants in the TCE Subregistry of the Volatile Organic Compounds Registry of the National Exposure Registries--persons with documented exposure to TCE through drinking and use of contaminated water. The health effects reported in excess by some or all of the sex and age groups studied were speech and hearing impairments, effects of stroke, liver problems, anemia and other blood disorders, diabetes, kidney disease, urinary tract disorders, and skin rashes.

The National Exposure Registry: analyses of health outcomes from the benzene subregistry.

The purpose of the National Exposure Registry is to assess the long-term health consequences to a general population from long-term, low-level exposures to specific substances in the environment. This study investigates the health outcomes of 1,143 persons (1,127 living, 16 deceased) living in south central Texas who had documented environmental exposure to benzene (up to 66ppb) in tap water. As with all subregistries, face-to-face interviews were used to collect self-reported information for 25 general health status questions. Using computer-assisted telephone interviewing, the same health questions were asked 1 year (Followup 1, F1) and 2 years later (Followup 2, F2). The health outcome rates for Baseline and Followup 1 and 2 data collections for the Benzene Subregistry were compared with national norms, that is, the National Health Interview Survey (NHIS) rates. For at least one of the three reporting periods, specific age and sex groups of the Benzene Subregistry population reported more adverse health outcomes when compared with the NHIS population, including anemia and other blood disorders, ulcers, gall bladder trouble, and stomach or intestinal problems, stroke, urinary tract disorders, skin rashes, diabetes, kidney disease, and respiratory allergies. Statistically significant deficits for the Benzene Subregistry population overall were found for asthma, emphysema, or chronic bronchitis; arthritis, rheumatism, or other joint disorders; hearing impairment; and speech impairment. No statistically significant differences between the two populations were seen for the outcomes hypertension; liver disease; mental retardation; or cancer. These results do not identify a causal relationship between benzene exposure and adverse health effects; however, they do reinforce the need for continued followup of registrants.

Recommendations for the statistical analysis of Chernoff/Kavlock test data.

The statistical analyses of the data related to the teratogenic testing of 60 compounds utilizing the Chernoff/Kavlock test are the basis of this paper. The hypotheses chosen to be tested and the statistical tests utilized to test those hypotheses are discussed. The topics explored are the use of comparisonwise error rate versus experimentwise error rate, the use of nonparametric tests versus more "conventional" parametric tests and the use of "historical data" in assessing and interpreting group difference.

Benzene--a review of the literature from a health effects perspective.

A literature review of the impact on human health of exposure to benzene was conducted. Special emphasis in this report is given to the health effects reported in excess of national norms by participants in the Benzene Subregistry of the National Exposure Registry--people having documented exposure to benzene through the use of benzene-contaminated water for domestic purposes. The health effects reported in excess (p < or = .01) by some or all of the sex and age groups studied were diabetes, kidney disease, respiratory allergies, skin rashes, and urinary tract disorders; anemia was also increased for females, but not significantly so.

Comparison of behavioral teratogenic effects of ethanol and n-propanol administered by inhalation to rats.

Despite extensive testing of ethanol, there has been little research on the reproductive effects of other alcohols. We investigated the behavioral teratogenicity of inhalation exposures to ethanol and n-propanol. Groups of 18 male (approximately 450 g) and 15 pregnant female Sprague-Dawley rats were exposed 7 hours/day for six weeks or throughout gestation, respectively, to 16 000, 10 000, or 0 ppm ethanol or to 7 000, 35 000, or 0 ppm n-propanol. Pregnant females exposed to 7 000 ppm n-propanol, but not to ethanol, showed reduced weight gain, and female offspring also had reduced weight gain through three weeks of age; there was also slight teratogenicity observed at this concentration. Exposed males were mated with unexposed females; fertility was reduced in males exposed to 7 000 ppm n-propanol (two viable litters from 17 matings), but there were no differences from controls in maternal weight gain, feed intake, or water consumption in any other groups. In both maternally- and paternally-exposed groups, litters were culled to four pups of each sex and fostered to untreated females. One female and one male pup per litter were administered tests of neuromotor coordination (ascent on wire mesh screen, rotorod), activity levels (open field, running wheel), or learning ability (avoidance, operant conditioning), but no significant differences from controls were found with either alcohol, despite the reduction in maternal and female offspring body weight and minimal teratogenicity with 7 000 ppm n-propanol. Calculations for predicting blood ethanol levels with inhalation exposure are also presented.

Developmental toxicity of diethylene glycol monomethyl ether (diEGME).

Diethylene glycol monomethyl ether (diEGME) was one of 15 glycols tested in CD-1 mice using a short-term in vivo reproductive toxicity assay (Chernoff/Kavlock test). Because results were strongly suggestive of potential reproductive toxicity, a teratology study was conducted in Sprague-Dawley rats. Time-mated females were orally dosed on Days 7-16 of gestation with diEGME in distilled water. Doses of 0, 1000, 1495, 2235, 3345, and 5175 mg/kg/day were used in a preliminary dose-finding study. At 5175 mg/kg/day, two of nine rats died, five of five litters were totally resorbed, and maternal extra gestational body weight gain was reduced. At 3345 mg/kg/day, six of nine litters were resorbed but there were no deaths and extra gestational body weight gain was not affected. Visceral and skeletal examinations revealed a dose-related increase in malformations, primarily of the ribs and cardiovascular system. Subsequently, pregnant rats were similarly dosed with 0, 720, or 2165 mg/kg/day. Neither dose was maternally toxic, but fetal body weights and the number of live implantations were significantly reduced at 2165 mg/kg/day. Rib malformations were seen in 9.1% (control), 42.9% (720 mg/kg/day, p less than 0.05), and 80.0% (2165 mg/kg/day, p less than 0.001) of litters. Cardiovascular malformations occurred in 0.0, 4.8, and 71.4% (p less than 0.001) of litters. Diethylene glycol monomethyl ether thus was teratogenic in rats at all doses tested, producing a dose-dependent series of malformations similar to those produced by other members of the glycol ether family.

Lack of selective developmental toxicity of three butanol isomers administered by inhalation to rats.

As part of an ongoing study of the developmental toxicology of industrial alcohols, this report presents the results of the teratology assessments of 1-butanol, 2-butanol, and t-butanol administered by inhalation to rats. Groups of approximately 15 Sprague-Dawley rats were exposed at 8000, 6000, 3500, or 0 ppm 1-butanol, 7000, 5000, 3500, or 0 ppm 2-butanol, or 5000, 3500, 2000, or 0 ppm t-butanol for 7 hr/day on Gestation Days 1-19 (sperm = 0). In each case, the highest concentration was selected to produce maternal toxicity. Dams were sacrificed on Gestation Day 20, and fetuses were individually weighed, tagged, and examined for external malformations. One-half of the fetuses were stained and examined for skeletal abnormalities, and the other half were examined for visceral defects using the Wilson technique. For each butanol isomer examined, the highest concentration (and the intermediate in some cases) was maternally toxic, as manifest by reduced weight gain and feed intake. Even at a maternally toxic dose, and in spite of a dose-dependent reduction in fetal weights for each isomer, the only teratogenicity observed was a slight increase in skeletal malformations (primarily rudimentary cervical ribs), seen with the highest concentration of 1-butanol. Thus, although teratogenicity was observed at 8000 ppm 1-butanol, and developmental toxicity was observed with each of the butyl alcohol isomers studied, concentrations 50 times the current permissible exposure limits for these three butanol isomers do not produce teratogenicity in rats.