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.

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.

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.

Neurophysiological and neuropathological evaluation of primates exposed to ethylene oxide and propylene oxide.

Over 500,000 workers in the United States are exposed to ethylene oxide and propylene oxide. These two solvents are used as chemical intermediates, as well as components in the manufacture of fumigants and food preparation. The neurophysiologic and neuropathologic effects of these two organic oxides were investigated in five groups of 12 primates after exposure to 50 or 100 ppm ethylene oxide, 100 or 300 ppm propylene oxide, or no chemical (sham-exposed). Animals were exposed for 7 h/day, 5 days/wk for 24 months. Body weights, electroencephalograms, and motor nerve conduction velocities of the sciatic and ulnar nerves were assessed six times throughout the exposure period. Although the monkeys exposed to 100 ppm ethylene oxide had significantly lower mean weights, nerve conduction velocities did not differ significantly among the groups. Following termination of exposures, ten animals (two from each exposure group) were sacrificed for neuropathological examinations. Multiple axonal bodies were found in the nucleus gracilis in seven of eight oxide-exposed animals, and demyelination was found in two monkeys exposed to ethylene oxide. In contrast, a single axonal body was found in one of the two sham-control monkeys. However, the lack of a dose-response relationship suggests that this effect may not be related to oxide exposure. In a follow-up study, nerve conduction velocity and neuropathology were assessed in the remaining monkeys seven years after exposure terminated, but again, treatment-related effects could not be detected.

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.

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.

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.

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.

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.

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.

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.

Evaluation of 60 chemicals in a preliminary developmental toxicity test.

The number of chemicals in commerce which have not been evaluated for potential developmental toxicity is large. Because of the time and expense required by conventional developmental toxicity tests, an abbreviated assay is needed that will preliminarily evaluate otherwise untested chemicals to help prioritize them for conventional testing. A proposed short-term in vivo assay has been used in a series of studies in which a total of 60 chemicals were tested. Some were independently tested two or four times each. In this preliminary test, pregnant mice were dosed during mid-pregnancy and were then allowed to deliver litters. Litter size, birth weight, and neonatal growth and survival to postnatal day 3 were recorded as indices of potential developmental toxicity. Results in this assay and conventional mouse teratology tests were generally concordant. Conventional data were available for 14 chemicals (ten teratogens, one fetotoxin, three nonteratogens), of which 11 (nine teratogens, one fetotoxin, one nonteratogen) produced evidence of developmental toxicity. This included conventional data for three chemicals (ethylene glycol, diethylene glycol dimethyl ether, and triethylene glycol dimethyl ether) that were untested before the present study. As high priority candidates for conventional testing on the basis of results here, all were subsequently studied in a standard teratology assay and were confirmed to be teratogenic in mice. Additionally, one of them (ethylene glycol) plus a fourth high priority candidate for conventional study (diethylene glycol monomethyl ether) were subsequently tested in rats and were found to be teratogenic in that species.

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.

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.

Carcinogenic effects of antimony trioxide and antimony ore concentrate in rats.

This study was initiated because of a suspected increase in incidence of lung cancer in antimony smelter workers in England. Three groups of 8-mo-old Wistar-derived rats (90 males and 90 females per group) were exposed by inhalation to either Sb2O3 [time-weighted average (TWA) 45 mg/m3], Sb ore concentrate (TWA 36 + 40 mg/m3), or filtered air (controls) for 7 h/d, 5 d/wk, for up to 52 wk and sacrificed 20 wk after terminating exposures. Serial sacrifices (5 rats/sex/group) were performed at 6, 9, and 12 mo. Autopsies and histopathological examinations were performed on all animals. The dusts and animal tissues were analyzed for Sb, arsenic, and other inorganic elements by atomic absorption and proton-induced X-ray emission methods. The most significant findings were the presence of lung neoplasms in 27% of females exposed to Sb2O3 and 25% of females exposed to Sb ore concentrate (p less than 0.01). None of the male rats in any group or the female controls developed lung neoplasms. There were no significant differences in incidences of cancer of other organs between exposed and control rats. These results were compared with other published results, including an animal inhalation study with Sb2O3 in which lung tumors were also induced. Higher concentrations of arsenic were found in tissues from female rats than from male rats. For example, arsenic levels in blood of control males, control females, Sb2O3 males, Sb2O3 females, Sb ore males, and Sb ore females were 60, 123, 115, 230, 71, and 165 micrograms arsenic/g dry blood, respectively, 9 mo after initiating exposures.

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.

Teratological assessment of methanol and ethanol at high inhalation levels in rats.

Alcohols are widely used as industrial solvents. In spite of the fact that ethanol is a human teratogen, there has not been systematic investigation of the potential teratogenic effects of other alcohols, particularly using the inhalation route of exposure, as would be appropriate in assessing occupational and environmental types of experience. As part of a large teratological examination of industrial alcohols, methanol and ethanol were administered by inhalation to groups of approximately 15 pregnant Sprague-Dawley rats. Methanol was administered at 20,000 ppm (20ME), 10,000 ppm (10ME), 5000 ppm (5ME), and 0 ppm (MECO) for 7 hr/day on Days 1-19 of gestation (Days 7-15 for 20ME). Ethanol was administered at 20,000 ppm (20ET), 16,000 ppm (16ET), 10,000 ppm (10ET), and 0 ppm (ETCO) for 7 hr/day on Days 1-19 of gestation. Dams were sacrificed on Day 20 (sperm = Day 0). One-half of the fetuses were examined using the Wilson technique for visceral defects, and the other half were examined for skeletal defects. The highest concentration of methanol (20ME) produced slight maternal toxicity and a high incidence of congenital malformations (p less than 0.001), predominantly extra or rudimentary cervical ribs and urinary or cardiovascular defects. Similar malformations were seen in the 10ME group, but the incidence was not significantly different from controls. No adverse effects were noted in the 5ME group. Dams in the 20ET group were narcotized by the end of exposure, and maternal weight gain and feed intake were decreased during the first week of exposure. The 16ET dams had slightly depressed weight gain (p less than 0.01) during the first week of exposure, but there were no significant effects on feed consumption. There was no definite increase in malformations at any level of ethanol, although the incidence in the 20ET group was of borderline significance.

Percutaneous penetration of benzene in hairless mice: an estimate of dermal absorption during tire-building operations.

Repeated skin contact with solvents containing as much as 0.5% benzene is common in workers building regular bias passenger tires. To estimate the amount of benzene absorbed through the skin of these workers, a series of in vivo studies was conducted in hairless mice. Percutaneous absorption, following single dermal applications of 14C-benzene contained in rubber solvent at a concentration of 0.5% (v/v), was calculated directly from the sums of radioactivity found in excreta, expired breath, and the carcass. Data from the study, together with observations made during tire-building operations, suggest that a worker could absorb 4-8 mg of benzene daily through the skin. This compares to 14 mg per day via inhalation at the NIOSH recommended standard of 1 ppm. Thus dermal absorption could contribute from 20-40% of the total benzene dose of these workers.