Effect of intrapartum meperidine on behavior of 3- to 12-month-old infant rhesus monkeys.

Potential long-term effects of intrapartum meperidine were studied in rhesus monkey infants whose dams received 0, 2, or 3 mg/kg meperidine, i.v., during labor (n = 5, 5, 3). Spontaneous behavior and cognitive performance were evaluated at 3-12 months of age. Observation of spontaneous behaviors indicated less age-related increase in quiet activities in drug-exposed infants. In the discrimination reversal test, drug-exposed infants had more balks (p = 0.008) and fewer correct choices (p = 0.008) during initial phases of the first reversal. Due to sex differences in the delayed alternation test, evaluation of drug effects on short-term memory was not possible. In the continuous performance test, drug-exposed infants performed better (NS) and had fewer omission errors (p = 0.034) during the second half of the test period. These initial findings suggest that short-term opiate exposure during labor can alter later behavior of infant monkeys.

Prioritizing candidate reproductive/developmental toxicants for evaluation.

To provide a rational method for the timely evaluation of possible reproductive/developmental toxicants, a prioritization scheme was developed by the California Department of Health Services to select chemicals for consideration by the Proposition 65 Scientific Advisory Panel. Initially, four ascertainment methods were used to identify and construct a master list of 164 candidate agents. Using two criteria, the potential for human exposure and the perceived reproductive/developmental hazard as judged by an ad hoc committee of experts, 42 candidates from the master list were identified as priority agents. For practical purposes, the 15 priority agents with the highest rankings will be given the highest priority in the review process. Limitations in the prioritization method used and refinements to be incorporated in an annual update are described.

Reproductive and developmental toxicity of toluene: a review.

Toluene is a widely used industrial solvent, and humans may also have high exposures to toluene from the deliberate inhalation ("sniffing") of paint reducer, paint thinner, or paint for their narcotic effects. A number of case reports describe neonatal effects that have been attributed to toluene abuse during pregnancy. These effects may include intrauterine growth retardation, premature delivery, congenital malformations, and postnatal developmental retardation. The possibility of exposures to other fetotoxic agents, either as impurities or admixtures in toluene-containing products, or by deliberate or accidental exposures to other chemicals or drugs, cannot be excluded in these cases. The fetotoxic effects of toluene have been demonstrated in controlled studies in animals and are comparable to those observed in humans who have abused toluene-containing products before or during pregnancy. Intrauterine developmental retardation is the most clearly established effect in animals, as evidenced by decreased late fetal weight and retarded skeletal development. There is also limited evidence in rodents for skeletal and kidney abnormalities, as well as some evidence for effects on postnatal physical and possibly neurobehavioral development. Estimated daily exposures from experimental studies in animals are compared to estimated human daily intakes at the occupational permissible exposure level and at the level reported to produce euphoria in humans. Acceptable human intakes under California's Proposition 65 and under U.S. Environmental Protection Agency procedures are discussed.

Reproductive toxicity of commercial PCB mixtures: LOAELs and NOAELs from animal studies.

This paper reviews the developmental/reproductive toxicity of commercial polychlorinated biphenyl (PCB) mixtures in animals and reports on the "no-observable-adverse-effect levels" (NOAELs) and "lowest-observable-adverse-effect levels" (LOAELs) from these studies. Identification of the lowest effective doses for reproductive toxicity of PCB mixtures is difficult because a variety of reproductive and developmental effects have been reported in several species using different commercial mixtures. Factors to be considered include sensitivity of the end point, sensitivity of species, study quality, biological plausibility, and relevance to humans. End points affected at the lowest doses (sensitive end points) included postnatal growth, development, and function. Among species for whom sensitive end points have been evaluated, a LOAEL of 0.25 mg/kg/day was identified for rodents on the basis of developmental delays in growth and behavioral function, and a LOAEL of 0.008 mg/kg/day was identified for nonhuman primates based on postnatal skin hyperpigmentation. NOAELs were not identifiable for these sensitive end points because effects were reported at the lowest doses tested.

Effect of intrapartum meperidine on the behavioral consequences of neonatal oxygen deprivation in rhesus monkey infants.

The endogenous opiate system is thought to play a unique role in the adaptive response to hypoxia during the fetal and neonatal period. Exogenous opiates used as analgesics during labor may also affect this adaptive response. Infant monkeys (Macaca mulatta) were exposed to oxygen deprivation (15-min period breathing 12% O2) on the day of birth. One half of the infants had been exposed to meperidine during parturition via treatment of the dam (2 mg/kg, i.v.). An additional control group received neither treatment. All infants were evaluated for growth, development and neurobehavioral performance over a subsequent 14-week period. Compared to controls, infants exposed to oxygen deprivation had somewhat slower weight gains during the early neonatal transition from weight loss to weight gain, were less responsive to sensory stimulation on the day of the oxygen deprivation episode, slept more on the first night after the episode, had fewer active and mature behaviors during a 3-week period of rapid motor development, and had impaired fine motor skills. Prior exposure to labor analgesia apparently prevented many of these effects. Use of opiate drugs during the perinatal period needs to take into account the unique properties and functions of the endogenous opiate system during this developmental period.

Effects of drugs on two-lever single-alternation performance in rats and mice(2).

The effects of d-amphetamine, chlorpromazine and pentobarbital on single alternation were compared in mice and rats. Chlorpromazine and d-amphetamine produced dose-related decreases in both accuracy and rate of responding with no differences in species sensitivity. Pentobarbital also produced dose-dependent decreases in accuracy and rate of responding in rats and on rate of responding in mice, but accuracy on the single alternation problem in mice was resistant to pentobarbital, even at doses that markedly reduced rate of responding. Higher doses of chlorpromazine, d-amphetamine and pentobarbital were required to produce effects in mice after trimethyltin exposure.

Neurobehavioral effects in offspring of mice given excess aluminum in diet during gestation and lactation.

Aluminum (Al) as Al lactate in a purified diet (25, 500 or 1000 micrograms Al/g diet) was fed to Swiss-Webster mice from conception through weaning. Weights, food intake and toxic signs were recorded at regular intervals and pregnancy outcome evaluated. Pups were assessed for growth, neurobehavioral development and toxic signs prior to weaning. Offspring were also evaluated with a multi-item neurobehavioral test battery immediately after weaning and again after a 2-week period during which they were all fed control (25 micrograms/g Al) diet. No maternal or reproductive toxicity was detected and there were no group differences in pup mortality, growth, toxic signs, or neurobehavioral development prior to weaning, with the exception of poor performance in a climbing test in the 1000 micrograms Al/g diet group. Parameters significantly affected by Al in the postweaning neurobehavioral testing were foot splay, forelimb and hindlimb grip strengths, and thermal sensitivity. Negative geotaxis was inconsistently affected and startle responses were not affected. These results show that maternal dietary exposure to excess Al during gestation and lactation which do not produce maternal toxicity can result in persistent neurobehavioral deficits in weanling mice.

The influence of high dietary aluminum on brain microtubule polymerization in mice.

One of the possible mechanisms that has been proposed to underlie the deleterious effects of excess aluminum on brain function is an impairment in the normal formation of the cytoskeletal network. Based on recent reports that aluminum can promote the in-vitro polymerization of purified tubulin, in the present study we characterized the effects of high dietary aluminum on in-vitro microtubule formation in brain supernatants. Mice were fed diets containing aluminum 25-1000 micrograms/g for up to 10 weeks. Tubulin polymerization in high-speed brain supernatants was not found to be affected by dietary aluminum. However, we observed that the addition of aluminum in vitro stimulated microtubule assembly in brain supernatants from mice fed control diets, as had been previously reported. Thus, impaired brain microtubule function is not an early general biochemical lesion in aluminum toxicosis.

Demography of penetrating cardiac trauma.

All cases of penetrating cardiac trauma in 1985 and 1986 in Jefferson County, Alabama, where patients dying of penetrating trauma received autopsies, were retrospectively reviewed. All hospitals in the county plus the single coroner's office provided the records of the 72 patients comprising this study. Incidents occurred most often in the home or residence (70%) by a known assailant (83%) due to domestic/social disputes (73%). Frequency was greatest in the evening hours (73% between 6:00 PM and 3:00 AM), on weekends in spring and summer. Victims tended to be male (86%), black (72%), married (46%), blue collar workers (62%). There were 41 (57%) gunshot wounds, 3 (4%) shotgun wounds, and 28 (39%) stab wounds with an associated mortality rate of 97%, 100%, and 68%, respectively. Prehospital mortality rate (dead at the scene) was 54.2% (39/72), and death on arrival was 26.4% (19/72), for a combined pretreatment mortality rate of 80.6%. All patients who arrived with no vital signs died. Mortality appeared to be related to mechanism of injury, age, race, sex, vital signs on arrival, number and specific cardiac chambers injured, associated major vascular injury, hematocrit, and mode of transportation. Mortality was not related to caliber of weapon, ethanol level, transport time, time from arrival to operation, or transfusion requirements. There were only ten survivors (1 gunshot wound and 9 stab wounds), all of whom had ventricular injuries and no associated major vascular injuries. The ten survivors represented a 71.4% (10/14) salvage rate for those victims arriving with vital signs. Complications occurred in three patients. Hospitalization averaged 7.3 days in the survivors. Penetrating cardiac trauma remains a serious, socially linked disease with a high rate of mortality. Rapid transport, aggressive resuscitation and cardiorrhaphy remain the best treatment.

Effects of aluminum ingestion on spontaneous motor activity of mice.

Aluminum (Al) as aluminum lactate in a purified diet was fed to adult female Swiss-Webster mice over a six week period. Comparison groups were: controls (CON), 25 micrograms Al/g diet; low Al (LO), 500 micrograms Al/g diet; high Al (HI), 1000 micrograms Al/g diet; and pair fed (PF) 25 micrograms Al/g diet pair fed to HI group. Weights, food intake and toxic signs were recorded at 3-day intervals and activity levels were measured during a 24-hr session during week 5 using an automated apparatus. Food intake was not reduced overall in Al-treated groups but they demonstrated a cyclic pattern of food intake. Mean weight gain over the 6-week period in the HI (0.5 g) and PF(0.1 g) groups was somewhat less than that in the CON (2.3 g) and LO (2.0 g) groups. No neurotoxic signs were recorded in any group, but a dose dependent increase in localized fur loss was seen. Overall activity level was 20% lower in HI than CON groups, with vertical movement more affected than horizontal movement. HI mice were less active during the diurnal period of peak activity than CON mice and their activity periods were also somewhat shorter (130 vs. 200 min). Activity of LO and PF mice did not differ significantly from controls, although PF activity levels were more variable. These data demonstrate that short term feeding of aluminum at levels within an order of magnitude of estimated human intake can influence neurobehavioral function as indexed by motor activity.

The influence of aluminum on resistance to listeria monocytogenes in Swiss-Webster mice.

Female, adult Swiss-Webster mice were fed, during gestation and subsequent lactation, diets containing either 25 (control), 500 or 1,000 micrograms Al/g diet in the form of Al lactate, followed by challenge with Listeria monocytogenes. Mice in the groups fed 1,000 and 500 micrograms Al/g had significantly lowered resistance to bacterial infection when compared to control animals (p less than 0.025). The animals given 1,000 micrograms Al/g also had higher concentrations of liver Al (p less than 0.05) than controls. Pups derived from these dams showed no differences in mortality rates or Al tissue levels. In contrast, nonpregnant animals fed 1,000 micrograms Al/g for 6 weeks had a slight decrease in mortality rate when compared to control animals. Dose-related changes in tissue Al levels were not observed in these adult, virgin mice. Finally, adult nonpregnant mice were injected subcutaneously with PBS only, or with 1, 5 or 10 mg of Al (in the form of Al lactate) per kilogram body weight followed by bacterial challenge. Animals which received 5 mg Al/kg had lower mortality rates to L. monocytogenes when compared to other treatment groups (p less than 0.025). This data suggests that Al has the potential to influence host resistance to bacterial infection depending on the physiological state of the host; it provides additional evidence for the role of Al as an environmental toxin.

Obstetric analgesia and infant outcome in monkeys: infant development after intrapartum exposure to meperidine or alfentanil.

Infant monkeys (Macaca mulatta) exposed to narcotic analgesics during labor after treatment of dams were evaluated for growth and development over a 14-week period. Ten infants exposed to meperidine (2 mg/kg maternal dose) or alfentanil (0.1 mg/kg maternal dose) were compared with seven controls whose dams received no analgesic. No group differences in weight gain or body growth were observed. Alfentanil-exposed infants appeared to have a higher incidence of infections requiring veterinary treatment. Measures of spontaneous activity showed a significantly higher incidence of immature rest pattern (laying) in the alfentanil group associated with lower overall locomotor activity relative to controls. Meperidine-exposed infants had a generally higher overall level of locomotor activity than controls that was statistically significant at 11 weeks of age. Alfentanil-exposed animals were impaired in performance of a simple cognitive task (object constancy) at 2 to 3 months of age and meperidine-exposed infants showed a similar nonsignificant trend. Gross and fine motor maturations were similar to those of controls. Thus, in this situation, the impact of obstetric analgesic treatment was demonstrable for several months after birth in some limited areas.

Effects of low-level lead exposure on 24 h activity patterns in the mouse.

Spontaneous activity of male mice chronically exposed to lead acetate or sodium acetate was tested for periods of 24 h in their home cages and normal housing groups. Animals receiving 0.25% lead acetate showed significantly higher levels of spontaneous activity than did distilled water controls during the early part of the dark phase in two experiments, and significantly lower activity levels during the latter part. Mice receiving 0.025% lead acetate were also significantly more active than controls early in the dark phase, and either significantly higher or no different from controls latterly. Animals receiving 0.025% sodium acetate were significantly less active than controls early in the dark phase, but later were equally active. Weight loss in lead-treated animals was variable and not correlated with changes in activity levels.

A labor readiness index (Bishop score) for rhesus monkeys.

A scoring system is presented for quantitative evaluation of labor readiness in macaque monkeys. Cervical position, length, softness and dilation are rated along with fetal head position for a total score of 13. The system is based on experience in evaluating readiness of multiparous rhesus monkeys for labor induction. Guidelines for the examination for use of the score are described.

Obstetric analgesia and infant outcome in monkeys. Neonatal measures after intrapartum exposure to meperidine or alfentanil.

Neurobehavioral evaluations were conducted in neonatal monkeys (Macaca mulatta) exposed to narcotic analgesics during labor through their dams. Infants exposed to meperidine (2 mg/kg maternal dose) or alfentanil (0.1 mg/kg maternal dose) were compared with controls whose dams received no analgesic. Meperidine and alfentanil differ in pharmacologic properties related to maternal-fetal transfer and neonatal metabolism. Drug-exposed infants showed neurobehavioral effects over the first 3 days of life including depressed respiration (at birth), depressed environmental response to aversive stimuli (days 0, 1, and 2), more overnight sleep (day 1), and more quiet behavior patterns while awake (day 3). In addition, drug exposure was associated with increased elicited muscle tone early in the neonatal period and earlier maturation of sitting, standing, and walking. No effects on growth or health were noted, but drug-exposed infants had lower hematocrits and an earlier onset of a linear growth rate as reflected in body weight. No qualitative or quantitative differences were noted between the two drug treatments. Because behavioral effects were seen after the drug was eliminated, a direct pharmacologic action of the drug does not fully explain the findings.

Effects of lead in the laboratory mouse. Development and social behaviour after lifelong exposure to 12 microM lead in drinking fluid.

The effects of chronic exposure to 12 microM lead, from conception onwards, on development and social behaviour were investigated in the laboratory mouse. Lead was administered as 0.25% solution of lead acetate in the drinking fluid. This level of exposure did not affect reproductive success, but caused decreased birthweight and retarded early development in offspring of treated dams. Mortality prior to weaning was significantly greater in pups treated with lead, and animals treated with lead had significantly reduced body weights throughout their lives. Levels of lead in tissues were greatly increased in all treated animals, with females showing significantly higher levels than males. Behaviour was assessed by ethological methods in paired encounters between unfamiliar animals in a novel environment. At age 3-4 weeks Exploratory Behaviour and Social Investigation were significantly increased and Immobility was significantly decreased in animals of both sexes treated with lead. Social Investigation was also increased at age 7-8 weeks but Exploratory Behaviour was decreased. At age 15-16 weeks Non-Social Activity was increased in males and decreased in females, although Social and Sexual Investigation was not affected in these male-female encounters. Lead-treated males, aged 17-18 weeks, showed significantly shorter latencies to aggression towards unfamiliar males than did controls.

Maternal and developmental toxicity of chronic aluminum exposure in mice.

The present study demonstrated aluminum-induced neurotoxicity in mouse dams and developmental retardation in their offspring following oral exposure to several dose levels during gestation and lactation. Female mice fed aluminum lactate (AL) at levels of 500 or 1000 ppm in their diet from Day 0 gestation to Day 21 postpartum were compared to mice which received a 100 ppm aluminum diet either ad libitum or pair-fed to the 1000 ppm AL group. Dams receiving the 500 and 1000 ppm AL diets showed signs of neurotoxicity beginning at Days 12-15 postpartum and showed significant weight loss. Offspring showed dose-dependent decreases in body weight (F = 6.47, p less than 0.001), crown-rump length (F = 7.37, p less than 0.0001), and ponderal index (F = 6.90, p less than 0.0002), at birth and preweaning. Absolute and relative liver and spleen weights were lower in pups from the high AL groups compared to controls (F = 3.34, p less than 0.025 and F = 15.54, p less than 0.001, respectively). Neurobehavioral development was somewhat delayed in aluminum-treated pups, but not in their pair-fed controls (F = 5.52, p less than 0.005). In addition to showing oral toxicity of excess AL during development dose-dependent toxic effects of parenteral aluminum exposure were demonstrated in pregnant mice which were injected subcutaneously with aluminum lactate solution at 10, 20, or 40 mg Al/kg body wt on Days 3, 5, 7, 9, 12, 13, and 15 of gestation. Maternal spleen and liver weights were significantly increased in aluminum treated animals (p less than 0.001 and p less than 0.05, respectively). Fetal crown-rump lengths were significantly reduced in the 20 mg/kg aluminum group (F = 9.79, p less than 0.001).

Effects of 1.2 microM lead in the laboratory mouse: developmental and behavioural consequences of chronic treatment.

Lead acetate, as a 0.025% (1.2 microM) solution in the drinking fluid, did not adversely affect the reproductive success in breeding mice, weights of pups at birth or cause delays in development. At 21 days, the treated offspring showed reduced weights but these returned to normal values in adulthood. Offspring of treated mice were given 1.2 microM lead acetate as drinking fluid after weaning. The mean daily intake of lead amounted to 2.4 and 2.6 mg/100 g body wt in females and males respectively and caused significant increases in the concentrations of lead in bone and brain. Sequestration of bone was greater in females than males. The behaviour of the offspring was examined by ethological analysis of social encounters between pairs of unfamiliar mice of similar treatment groups in a neutral cage. Evidence of enhanced reactivity to the test situation was seen in treated males at age 3-4 weeks by increased social investigation during the first 3 min of the 20 min encounter, at 7-8 weeks by decreased immobility in the final 5 min of the test and at 18-19 weeks by an increased duration of exploratory behaviour. However, when encountering females at 30-31 weeks, the treated males showed more immobility than did the controls. Treated females at 3-4 weeks, in the first 3 min of the test, showed a decreased frequency of exploratory behaviour and increased immobility, but at 7-8 and 18-19 weeks they showed enhancement of social and sexual investigation. Behaviour was unaltered at 30-31 weeks in encounters with unfamiliar males.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of lead in the laboratory mouse. 1. Influence of pregnancy upon absorption, retention, and tissue distribution of radiolabeled lead.

Whole-body retention and excretion following a single oral dose of radiolabeled lead (203Pb) in chronically lead-exposed pregnant BK:W mice were examined over 10-13 days. This was compared with values in similarly treated nonpregnant females and in ip injected females. Whole-body and bone retention were greater in injected than in orally dosed nonpregnant females; gastrointestinal absorption was estimated from this difference. Whole-body retention in the pups was measured at birth and at the end of the experiment. Whole-body retentions in pregnant females and in their pups at birth were significantly raised after treatment at Gestational Day 17, but not after treatment at Gestational Day 11, 14, 20, 23, or 26. Pup body burdens at birth were significantly and positively correlated with maternal retention. Measurement of radioactivity in bone, kidney, brain, heart, and liver of adults at the end of the experiments showed significantly increased levels in bone and kidney from females treated at Gestational Day 17 and in bone from females treated at Gestational Day 11. Lead excretion did not differ significantly among the groups but the total lead content of the femur was significantly raised in females treated at Gestational Days 17 and 26. Thus, these experiments provide evidence that lead absorption and retention in mice are markedly increased in the latter stages of pregnancy.

Effects of preoperative medications on gastric pH, volume, and flora.

Aspiration of acid gastric juice poses a potential threat during operations. Many anesthesiologists use a variety of agents aimed at decreasing gastric volume and/or acidity. The effect of three agents on gastric volume, pH, and flora, and the effect of cefazolin on gastric flora in morbidly obese patients were studied. Cefazolin did not sterilize the gastric lumen. Almost one-half of patients not treated with an H2 blocker had a pH below 2.5 and a gastric volume of 20 ml or more. Five had both a low pH and significant volume and, thus, the potential for lethal aspiration. Two doses of cimetidine, 300 mgm orally, or of ranitidine, 150 orally, the evening before and the morning of operation decreased gastric volume and raised pH reliably to a level that should be protective from fatal aspiration. However, gastric cultures after these drugs were positive 86% of the time with a larger variety of organisms than in the untreated stomachs. Metoclopramide failed to decrease gastric volume or raise pH. Transoperative cefazolin was used in all patients. Clinical infection was not a problem.