Neurobehavioral test performance in the third National Health and Nutrition Examination Survey.

The third National Health and Nutrition Examination Survey (NHANES III) contained three computerized neurobehavioral tests from the Neurobehavioral Evaluation System (NES): simple reaction time, symbol-digit substitution and serial digit learning. The neurobehavioral data that were collected came from a nationally representative sample of adults 20-59 years old. Performance on the tests was related to sex, age, education level, family income and race-ethnicity. Performance decreased as age increased, and increased as education level and family income increased. Differences in performance between sexes, levels of education and racial-ethnic groups tended to decrease as family income increased. The relationship between age and performance on the symbol-digit substitution test varied by education level and by racial-ethnic group. The relationship between age and performance on the serial digit learning test varied by racial-ethnic group. Questionnaire variables that were related to performance on one or more of the tests included the reported amount of last night's sleep, energy level, computer or video game familiarity, alcoholic beverages within the last 3 h and effort. Persons who took the tests in English or Spanish performed differently on the symbol-digit substitution and serial digit learning tests. Performance on all the tests decreased as test room temperature increased.

Evaluation of postural stability in workers exposed to lead at a secondary lead smelter.

Postural sway testing was carried out on a group of 145 workers exposed to lead in a secondary lead smelter and 84 workers not exposed to lead in a hinge manufacturing plant. All workers were measured for blood lead levels (BLL) and erythrocyte zinc protoporphyrin (ZPP) concentrations at the time of testing and both a total cumulative and a time-weighted average BLL value was constructed for the lead exposed workers. The lead exposed workers mean BLL at the time of testing was 38.9 microg/dl and the non-exposed workers mean was 2.3 microg/dl. ZPP levels averaged 55.2 microg/dl for exposed workers and 18.9 microg/dl for non-exposed workers. Total cumulative BLL averaged 83476 microg/dl days for the exposed workers, with a mean time-weighted average BLL of 35.1 microg/dl. Six tests of postural stability, four two leg conditions and two single leg conditions were administered to all subjects using a force platform to produce measurements of sway for comparison purposes. The two leg conditions also manipulated the visual and proprioceptive systems. A statistically significant association was observed for sway measurements and the current BLL for all workers, but not with the current BLL of only the lead exposed workers. No statistically significant associations were present with the cumulative measures of long-term exposure. Of the six tests of sway, only the single leg conditions showed significant exposure effects. The results suggest effects of lead exposure among those with average BLL near 40.0 microg/dl, but only in the most challenging one leg conditions.

The IPCS Collaborative Study on Neurobehavioral Screening Methods: III. Results of proficiency studies. Steering Group.

The goal of the IPCS Collaborative Study on Neurobehavioral Screening Methods was to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories world-wide. The first phase of the Collaborative Study involved training the participants: evidence of training was then evaluated using positive-control compounds. The positive-control studies required the laboratories to identify, using the FOB, specific neurotoxic syndromes produced by acute exposure to p,p'-DDT, parathion, and by short-term repeated dosing with acrylamide. For the sake of expediency, only one dose of each chemical was used instead of collecting dose-response data. Motor activity test chambers were not of uniform design. The laboratories were therefore required to demonstrate adequate sensitivity by the ability to detect statistically-significant activity increases and decreases produced by triadimefon and chlorpromazine, respectively, following acute administration of a range of doses. The resulting FOB and motor activity data showed variability in the magnitude of effects obtained: some of these differences were attributed to miscommunications, difficulties with the techniques or protocol, or the limitations of having only one dose. All laboratories, however, successfully met the criteria set forth by the Study Steering Committee.

The IPCS Collaborative Study on Neurobehavioral Screening Methods: IV. Control data. Steering Group.

The goal of the International Programme on Chemical Safety (IPCS) Collaborative Study on Neurobehavioral Screening Methods was to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories worldwide. The control data were crucial to the outcome of the studies in terms of sensitivity and reliability of the test measures, which in turn impact on the between-laboratory comparisons of chemical effects. In addition, analyses of control data can aid in determining endpoints that may require modification to improve their sensitivity and reliability. The control data from the eight laboratories were examined in terms of the following parameters: 1) control variability within studies for each laboratory; 2) within-laboratory replicability of control values across studies; 3) within-laboratory stability of control values over the course of testing for a given study; and 4) between-laboratory comparisons of parameters (1), (2), and (3). The analyses indicated considerable differences across endpoints, wherein some measures showed high variability and little replicability, while others were extremely reproducible. Generally, there were similar ranges of variability and replicability of control data across laboratories, although in some cases one or two laboratories were markedly different from the others. The physiological (weight, body temperature) and neuromuscular (grip strength, landing foot splay) endpoints exhibited the least variability, whereas the subjective assessments of reactivity varied the most. These data indicate a reasonable degree of comparability in the data generated in the participating laboratories.

The IPCS Collaborative Study on Neurobehavioral Screening Methods: V. Results of chemical testing. Steering Group.

The IPCS Collaborative Study on Neurobehavioral Screening Methods was undertaken to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories world-wide. Following the training phase and the conduct of proficiency studies in all laboratories, participants proceeded to test the effects of seven chemicals in both single dose and four-week repeated dosing scenarios. The chemicals studied were acrylamide, bisacrylamide, p,p'-DDT, lead acetate, parathion, toluene, and triethyl tin. Participants received coded samples from a common source. In order to judge the general utility of these procedures in a diversity of testing situations, laboratories conducted the studies under their standard conditions, using their choice of rat strain and test equipment. Chemical does and time of peak effect for acute testing were determined by each laboratory: these parameters were quite similar for some chemicals, but varied greatly for others. The results of the chemical tests indicated that while there was some variability in the data on specific endpoints, all laboratories detected and characterized the effects of all but one of the known neurotoxicants. The one exception (toluene) was probably due to other factors (e.g., dose level, route of administration) rather than lack of sensitivity of the test methods. This study provides extensive data regarding the use of neurobehavioral screening methods over a range of laboratory conditions as well as the reliability, sensitivity, and robustness of the tests to detect neurotoxic potential of chemicals.

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.

Marked increase in the teratogenicity of the combined administration of the industrial solvent 2-methoxyethanol and radiofrequency radiation in rats.

Limited published animal research reports synergistic teratogenic effects following combined hyperthermia (induced by elevated ambient temperature) and administration of chemical teratogens. Radiofrequency (RF) radiation is widely used in occupational environments. Since RF radiation also elevates the body temperature of, and is teratogenic to, exposed animals, concurrent RF radiation and chemical agent administration may enhance teratogenicity. The present exploratory study, consisting of preliminary dose-finding studies and the primary study, was designed to investigate whether concurrent exposure of rats to RF radiation and the industrial solvent 2-methoxyethanol (2ME) can enhance the developmental toxicity of either agent acting alone. Preliminary dose-finding studies using small numbers of rats investigated the ability of various RF radiation conditions and doses of 2ME to produce external malformations (primarily of the paws) when administered on gestation day 13. Based on these preliminary studies, RF radiation exposure [sufficient to elevate rectal temperature to 42.0 degrees C (4 degrees C above normal for rats) for 30 min] and 2ME administration (150 mg/kg) were selected for the primary study. In the primary study, groups of 18 to 27 pregnant rats were administered RF radiation exposure and distilled water gavage, 2ME gavage and sham RF exposure, RF radiation exposure and 2ME gavage concurrently, or sham RF exposure and distilled water gavage. Pregnant rats were sacrificed on gestation day 20, and the offspring were examined for external malformations. Combined exposures enhanced the adverse effects produced by either experimental agent alone (no malformations were detected in the double sham group). Mean fetal malformations/litter increased from 14% after 2ME and sham RF (15/26 litters affected, with an average of 2 fetuses/litter malformed) and 30% after RF radiation and water gavage (10/18 litters affected, with an average of 4 fetuses/litter malformed), to 76% after the combined treatment (18/18 litters affected, with an average of 12 fetuses/litter malformed). In addition to a significant increase in the frequency of malformations, the severity of malformations also was enhanced by the combination treatment (on a relative severity ranking scale, the 2ME severity score was less than 1, the RF score was 3, and the combination score was 6). This study provided evidence of synergism between RF radiation and 2ME administration, but additional research will be required to characterize the extent of synergism between these two agents. Potential interactive effects between chemical and physical agents need to be investigated to determine the extent to which such interactions should impact occupational exposure standards.

Effects of elemental mercury exposure at a thermometer plant.

This study compares 84 mercury-exposed workers at a thermometer manufacturing facility with 79 unexposed workers for evidence of chronic mercury toxicity. Personal breathing-zone air concentrations of mercury ranged from 25.6 to 270.6 micrograms/m3 for thermometer workers. Urinary mercury levels in the study population ranged from 1.3 to 344.5 micrograms/g creatinine, with eight (10%) participants exceeding 150 micrograms/g creatinine and three workers exceeding 300 micrograms/g creatinine, which indicates increased absorption of mercury among the thermometer workers. All urine mercury levels in the comparison group were compatible with normal background levels in unexposed adults (less than 10 micrograms/g creatinine). Thermometer plant workers reported more symptoms than did controls; in general, these differences were not statistically significant and could not be specifically associated with mercury exposure. Static tremor, abnormal Romberg test, dysdiadochokinesia, and difficulty with heel-to-toe gait were more prevalent among thermometer workers than control workers, which could not be associated with recent mercury exposure; there was some suggestion of an association with chronic exposure. There were no intergroup differences for the standard clinical tests of renal function except for a significantly higher mean specific gravity among the thermometer workers. A positive correlation was found, however, between urinary N-acetyl-b-D-glucosaminidase (NAG) and urinary mercury. There was no consistent evidence for intergroup differences in proximal renal tubule function, as measured by urinary beta 2-microglobulin (B2M) or retinol binding protein (RBP).

Developmental toxicology of industrial alcohols: a summary of 13 alcohols administered by inhalation to rats.

The developmental toxicology of 13 industrial alcohols (methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, tertiary-butanol, 1-pentanol, 1-hexanol, 2-ethyl-1-hexanol, 1-octanol, 1-nonanol, and 1-decanol), and the behavioral teratogenicity of 4 of these alcohols, were assessed in a series of experiments. The results of individual alcohols have been published previously, but the present paper summarizes the results in view of structure-activity relationships among these alcohols. The alcohols were administered by inhalation for 7 hours per day (6 hours/day for 1-decanol) on gestation days 1-19 to groups of approximately 15 pregnant Sprague-Dawley rats. For developmental toxicology evaluations, dams were sacrificed on gestation day 20. Fetuses were serially removed, weighed, sexed, and examined for external malformations. The frequency of visceral malformations and variations was determined in one-half of the fetuses, and the frequency of skeletal deviations was determined in the other half. Behavioral teratology endpoints were investigated in groups of 15 pregnant rats exposed to one of four alcohols (ethanol, 1-propanol, 1-butanol, and tertiary-butanol) and also involved groups of 18 male rats which were exposed to the same concentrations of each alcohol for 6 weeks, and then mated to untreated females. In the behavioral teratology evaluations, all litters were culled to eight pups and fostered to unexposed mothers. Offspring were tested from days 10-90 on a series of behavioral tests designed to evaluate neuromotor integrity, activity levels, learning, and memory. Additionally, brains were removed from 10 offspring per group at 21 days of age, and were dissected into cerebrum, cerebellum, brainstem, and midbrain; these samples were assayed for steady-state levels of protein and the neurotransmitters acetylcholine, dopamine, norepinephrine, 5-hydroxytryptamine (serotonin), substance P, B-endorphin, and met-enkephalin. Congenital malformations were noted for methanol, 1-propanol, isopropanol, and 1-butanol, but only at concentrations in excess of 5000 ppm. These concentrations also produced toxicity in the maternal animals; thus, there was little evidence of selective developmental toxicity among the alcohols. Although sporadic behavioral and neurochemical deviations were detected, no consistent pattern of effects was seen for any of the alcohols we tested. It should be noted that alcohols with chain lengths longer than the butyl series could not be generated as vapors at sufficiently high concentrations to produce observable toxicity in the maternal animals. This limits the generality of these findings to the possible developmental effects of these alcohols when taken through other routes of exposure.(ABSTRACT TRUNCATED AT 400 WORDS)

Behavioral teratology investigation of 1-butanol in rats.

Two concentrations of 1-butanol (3000 and 6000 ppm) were administered by inhalation to separate groups of 15 pregnant Sprague-Dawley rats for 7 hr per day throughout gestation; 18 male rats were similarly exposed for 7 hr per day for 6 weeks, and mated to unexposed females. Litters were culled to 4 female and 4 male pups and fostered to untreated controls. From days 10-90, offspring were tested as follows: a) ascent on a wire mesh screen, b) rotorod, c) open field and photoelectrically-monitored activity, d) running wheel, e) avoidance conditioning, and f) operant conditioning. Additionally, brains from 10 offspring at 21 days of age were dissected into cerebrum, cerebellum, brainstem, and midbrain. Each sample was assayed for protein and the neurotransmitters acetylcholine, dopamine, norepinephrine, serotonin, met-enkephalin, beta-endorphin, and substance P. Overall, there were few behavioral or neurochemical alterations detected in the offspring following maternal or paternal exposure to either 3000 or 6000 ppm 1-butanol. This scarcity of effects is important to risk assessment extrapolations drawn from ethanol. Based on the structural similarity of 1-butanol to ethanol and long-standing observations that toxicity to adult animals generally increases with chain length among the alcohols, significant behavioral and neurochemical deviations were predicted. The scarcity of effects from butanol needs to be accounted for in hypotheses relating toxicity to alcohol chain length and in risk assessment extrapolations from findings with ethanol.

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.

Neurobehavioral evaluation of soil and structural fumigators using methyl bromide and sulfuryl fluoride.

Neurobehavioral functions affected by methyl bromide exposure were evaluated in California structural and soil fumigators using methyl bromide and sulfuryl fluoride. Sampling data revealed that structural fumigators are exposed for up to 1.5 hrs/day to 0-2.2 ppm methyl bromide and/or 10-200 ppm sulfuryl fluoride, and soil fumigators can be exposed to 2.3 ppm methyl bromide over an 8-hr day. Subjects were grouped for statistical analysis on the basis of exposure history: Those exposed primarily (80% or more of the work period with exposure potential) to methyl bromide (N = 32), primarily to sulfuryl fluoride (24), or to a combination of methyl bromide and sulfuryl fluoride (40-60% of each) for a minimum of one year (18), and those not exposed to high concentrations of any chemicals (29 Referents). Fumigators using methyl bromide reported a significantly higher prevalence of 18 symptoms consistent with methyl bromide toxicity than did Referents. Methyl bromide fumigators did not perform as well as Referents on 23 of 27 behavioral tests (chosen to reflect methyl bromide effects), and were significantly lower on one test of finger sensitivity and one of cognitive performance. These consistent differences suggest that even the low levels of methyl bromide found in fumigation today may produce slight neurotoxic effects. found in fumigation today may produce slight neurotoxic effects. The greater number of symptoms and reduced performance on all cognitive tests in sulfuryl fluoride fumigators compared to the Reference Group plus the absence of published research on this compound suggest that the data base for sulfuryl fluoride is inadequate.

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.

Comparative inhalation teratogenicity of four glycol ether solvents and an amino derivative in rats.

Previous research demonstrated the inhalation teratogenicity of the solvent 2-ethoxyethanol in rats and rabbits. As this is one of a class of widely used industrial solvents, we investigated the teratogenicity of five structurally related compounds. Each chemical was vaporized and administered to approximately 15 pregnant rats in one to three concentrations for 7 hr/day on gestation days 7 to 15, and dams were sacrificed on day 20. Fetuses were individually weighed, and two-thirds of them were fixed in Bouin's solution and examined for soft-tissue anomalies. The other one-third were fixed in alcohol, stained with Alizarin Red and examined for skeletal defects. Data were analyzed on a litter basis; three solvents were compared with a pooled group (N = 34) of sham-exposed controls, and the remaining two were compared with a group of 15 controls. At concentrations which were apparently not maternally toxic, 2-methoxyethanol was highly embryotoxic, producing complete resorptions at 200 ppm; increased resorptions, reduced fetal weights and skeletal and cardiovascular defects occurred at both 100 and 50 ppm. 2-ethoxyethyl acetate at 600 ppm induced complete resorption of litters; 390 ppm reduced fetal weights and induced skeletal and cardiovascular defects, but only a single defect was observed at 130 ppm. 2-Butoxyethanol evidenced slight maternal toxicity at 200 ppm but produced no increase in congenital defects at that concentration. Neither 2-(2-ethoxyethoxy)ethanol (100 ppm) nor 2-methylaminoethanol (150 ppm) was maternally toxic or embryotoxic. In summary, shorter alkyl chained glycol ethers produced greater embryotoxicity than those having longer chains, and the ester produced effects equivalent to the ether, both patterns predictable from the biochemical literature.

Reproductive toxicity of the industrial solvent 2-ethoxyethanol in rats and interactive effects of ethanol.

The solvent, 2-ethoxyethanol, induced complete embryomortality in pregnant rats exposed to three times the current Federal permissible exposure limit (PEL). Following exposure to ethoxyethanol at a concentration only one-half the current PEL, the offspring evidenced behavioral and neurochemical deviations from controls. Subsequent studies found that ingestion of ethanol with concomitant inhalation of ethoxyethanol vapors early in pregnancy appeared to reduce the number of both behavioral and neurochemical deviations found for ethoxyethanol. In contrast, the concomitant exposure to ethanol and ethoxyethanol later in gestation potentiated the behavioral and neurochemical effects of ethoxyethanol. This research indicates that the industrial solvent 2-ethoxyethanol presents an occupational reproductive hazard and raises the issue of the importance of an interaction of social habits with occupational exposure to such hazards. The results would suggest that occupational physicians should advise pregnant workers in the chemical industry of the adverse effects of ethanol during pregnancy and of the possible interactions with other chemicals and should encourage them to be especially cautious with ethanol consumption since they may be at greater risk.

Behavioral teratology of ethylene glycol monomethyl and monoethyl ethers.

A recent addition to the field of teratology has been the inclusion of functional assessment techniques of offspring after prenatal exposure to exogenous agents. The present paper reviews the behavioral teratogenic effects of ethylene glycol monomethyl ether (EGME, 2-methoxyethanol) and ethylene glycol monoethyl ether (EGEE, 2-ethoxyethanol). Groups of 15 pregnant Sprague-Dawley rats were exposed via inhalation to 25 ppm EGME or to 100 ppm EGEE on gestation days 7 to 13 or 14 to 20. An equal number of sham-exposed controls were included for both periods of gestation. The only effect noted in the maternal animals was a slightly prolonged gestation in the group exposed to 100 ppm EGEE on days 14 to 20. Litters were culled to four female and four male pups on the day of birth. Pups of each sex from all litters were tested on a variety of behavioral tasks (including tests of neuromuscular ability, activity, and learning ability) extending from postnatal days 10 to 90. In addition, brains from newborn and from 21-day-old offspring were removed and analyzed for concentrations of the neurotransmitters acetylcholine, dopamine, norepinephrine, and 5-hydroxytryptamine (serotonin). Both the behavioral testing and the neurochemical evaluations revealed functional alterations in the litter groups experiencing prenatal exposure to EGME and EGEE at concentrations which produced no observable effects in the maternal animals.