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Behavioral thresholds to pure tones were obtained from adult rhesus monkeys that had been exposed to lead during early development and unexposed cohort controls. Thresholds were elevated (by 2-9 dB) for the previously lead exposed monkeys at all frequencies tested (125-8,000 Hz in octave steps). Although the magnitude and direction of the differences were similar to significant effects reported for children, the more difficult task and much smaller sample sizes in this study of monkeys may have precluded obtaining significant differences at the same magnitude of effects observed in children. Thresholds for one lead-exposed monkey were significantly elevated at midrange frequencies in agreement with electrophysiological results obtained in another study [Lasky, Maier, Snodgrass, Hecox, and Laughlin [1995] Neurotoxicology and Teratology, 17, 633-644]. Behavioral measurements during the threshold task indicated less engagement for lead exposed monkeys than for controls. In addition, the lead exposed monkeys completed testing at significantly fewer frequencies and were significantly more difficult to test than control monkeys by tester ratings. These results are consistent with reports concerning the behavior of lead exposed children., ((c) 2009 Wiley Periodicals, Inc.)

High lead levels adversely affect visual function in humans and laboratory animals. The effects of lower lead levels are less certain. This study compared the development of photopic spatial acuity in rhesus monkeys exposed to lead (n = 43) with monkeys (n = 23) not exposed to lead. Lead exposure began at Day 8 postpartum and continued daily throughout the first 26 weeks of postnatal life achieving target blood lead levels of 35-40 microg/dl by about 15 weeks. Photopic spatial acuity was evaluated by a preferential looking technique used clinically to assess spatial acuity in human infants. Acuity increased rapidly over the first few postnatal weeks achieving the maximum acuity level assessed (26.3 c/deg) by 7 weeks of age for most monkeys. Postnatal lead exposure at the dosages and durations studied did not affect the development of photopic spatial acuity., ((c) 2008 Wiley Periodicals, Inc.)

Evaluation of sensory processing function serves as a critical component of treatment planning and implementation of intervention in pediatric occupational therapy practice. We developed a Sensory Processing Scale for Monkeys (SPS-M), based on human tests, that measures behavioral responses to a series of tactile stimuli. This assessment has been used to assess sensory processing in adult rhesus monkeys exposed to prenatal alcohol, stress, or postnatal lead. Control monkeys from undisturbed pregnancies showed a habituation pattern, prenatally stressed monkeys showed sensitization, and prenatal alcohol-exposed monkeys showed relatively high responsiveness without habituation across trials. Lead-exposed monkeys showed sensitization compared to nonlead-exposed controls, and chelation reduced the sensitization in lead-exposed animals. Aversive responsiveness was associated with up-regulated striatal dopamine receptor binding measured with positron emission tomography.

Little is known about direct effects of exposure to lead on central nervous system development. We conducted volumetric MRI studies in three groups of 17-year-old rhesus monkeys: (1) a group exposed to lead throughout gestation (n = 3), (2) a group exposed to lead through breast milk from birth to weaning (n = 4), and (3) a group not exposed to lead (n = 8). All fifteen monkeys were treated essentially identically since birth with the exception of lead exposure. The three-dimensional MRI images were segmented on a computer workstation using pre-tested manual and semi-automated algorithms to generate brain volumes for white matter, gray matter, cerebrospinal fluid, and component brain structures. The three groups differed significantly in the adjusted (for total brain size) volumes of the right cerebral white matter and the lateral ventricles. A significant reduction was noted in right cerebral white matter in prenatally exposed monkeys as compared to controls (p = 0.045). A similar reduction was detected in the white matter of the contralateral hemisphere; however, this difference did not achieve statistical significance (p = 0.143). Prenatally exposed monkeys also had larger right (p = 0.027) and left (p = 0.040) lateral ventricles. Depending on the timing of exposure during development, lead may exhibit differential effects with resultant life-long alterations in brain architecture.

The Harlow Center for Biological Psychology (HCBP) has a cohort of rhesus monkeys that were exposed to low concentrations of lead acetate in utero or as infants. The lead-exposed animals have been followed for 19 years and have developed four cases of inguinal hernia (males), three cases of endometriosis (females), and one case of immunoblastic lymphoma (male). Retrospective analysis of the data from the original lead-exposed cohort indicates that there is a significant association between lead exposure and the development of inguinal hernia (P=.04). Endometriosis was not significantly associated with lead exposure (P=.36). A case control study also was done to determine the significance of neonatal lead exposure as a risk factor for the development of inguinal hernia and endometriosis. The risk of developing inguinal hernia was significantly increased in lead-exposed animals (OR=20.0, P=.009). The association between endometriosis and lead exposure was also strong (OR=10.13, P<.001). No unmatched variables were associated with inguinal hernia, including body weight, history of diarrhea, constipation, or intussusception. No unmatched variables were highly associated with endometriosis, including body weight, age at first parity, and history of stillbirths. However, parity and the number of stillbirths were associated with lead exposure (P=.011 and P=.041, respectively). There was an association between endometriosis and a history of hysterotomy (OR=2.09) but it was not statistically significant (P=.38). No other cases of lymphoma in unexposed animals were identified using HCBP animal health records. These data indicate that early lead-exposed rhesus monkeys may develop illnesses later in life, especially inguinal hernia and endometriosis, more frequently than unexposed monkeys. Studies of human populations with early lead exposure are warranted to determine their incidence of inguinal hernia, endometriosis, and hematologic neoplasia.

Sixty-six female rhesus monkeys were randomly assigned to three lead exposure conditions (none, from birth to 1 year, and from birth to 2 years) by two chelation treatment (succimer and no succimer) conditions. Blood lead levels were maintained at 35-40 microg/dl beginning shortly after birth and continuing for 1 or 2 years postnatally. There were two separate chelation regimes: 53 and 65 weeks of age. Lead and lead-vehicle dosing were discontinued while succimer was administered. Succimer (or placebo) was administered orally at a dose of 30 mg/kg/day (divided into three doses per day) for 5 days and for 14 additional days at 20 mg/kg/day (divided into two doses per day) for a total 19-day treatment regimen. Auditory function was assessed in these monkeys at least 1 year after lead intake had been discontinued. The outcome measures included tympanometry to assess middle ear function, OAEs to assess cochlear function, and ABRs to assess the auditory nerve and brainstem pathways. There were no significant differences as a function of succimer treatment for any of the tympanometric variables measured. Suprathreshold and threshold distortion product otoacoustic emissions were comparable among the succimer and vehicle groups. However, there was a nonsignificant trend to smaller amplitude distortion products at the highest frequencies assessed (6.4-10.0 kHz). Finally, the auditory evoked response at levels from the auditory nerve to the cerebral cortex did not significantly differ as a function of succimer treatment.

Seventy-two female rhesus monkeys were randomly assigned to three lead exposure conditions (none, birth to 1 year, birth to 2 years). In a completely crossed design, the lead-exposed and control monkeys were randomized to placebo or chelation therapy which began at 1 year of age. Dosing was conducted daily beginning on day 8 postpartum. The lead dose levels were adjusted biweekly to gradually elevate the blood lead level of each monkey to a target of 1.69-1.93 micromol/L (35-40 microg/dL). Succimer (or placebo) was administered orally (30 mg/kg/day for 5 days and 20 mg/kg/day for 14 additional days) for a total 19-day treatment regimen. There were two separate chelation regimes at 53 and 65 weeks of age. Succimer therapy in combination with lead abatement reduced blood lead levels significantly faster than lead abatement alone; however, that advantage disappeared once succimer therapy was discontinued. Weight, crown-rump length, and head circumference were measured regularly. Growth in weight, length, and head circumference did not vary significantly as a function of blood lead levels. Succimer chelation therapy did not significantly affect weight, length, or head circumference through 2 years of age., (Copyright 2001 Academic Press.)

Myeloid neoplasia has been studied extensively in human beings but has not been reported in macaques. A 2-year-old female rhesus macaque that was experimentally exposed to lead as a neonate, was noted to have immature circulating myelocytic cells, including 1% blasts, and normocytic normochromic anemia on a blood sample obtained for monthly health monitoring. The animal was treated with hydroxyurea, blood transfusion, and recombinant human erythropoietin to reduce the leukocytosis and correct the anemia. The disease had a relatively indolent course for 3 months, when it progressed to blast crisis. After the onset of blast crisis, the animal was euthanized because of bleeding problems, anemia, and a progressive decline in her health. The animal was negative by serology, polymerase chain reaction (PCR) assays, and/or culture for simian retrovirus (SRV), simian T-lymphotropic virus type I (STLV-I), and simian immunodeficiency virus (SIV). PCR assay for the bcr-ABL chromosomal translocation using primers made for the human gene was negative. Serology for Epstein-Barr virus (EBV)-like viruses was positive for IgG directed against the viral nucleocapsid antigen, but epidemiologic factors make it unlikely that the leukemia was associated with EBV-induced viral transformation. Lead exposure has been associated with neoplasia in human beings, and the possible role of neonatal lead exposure in hematologic neoplasias deserves further scrutiny.

Although succimer (Chemet, meso-2,3-dimercaptosuccinic acid, DMSA) is considered to be a safe and effective chelating agent for the treatment of lead poisoning in humans, there is concern that it may increase the gastrointestinal (GI) absorption and retention of Pb from exposures suffered concurrent with treatment. This concern is justified because the availability of Pb-safe housing during outpatient treatment with oral succimer is limited. We used a juvenile nonhuman primate model of moderate childhood Pb intoxication and a sensitive double stable Pb isotope tracer methodology to determine whether oral succimer chelation affects the GI absorption and whole-body retention of Pb. Infant rhesus monkeys (n = 17) were exposed to Pb daily for 1 year postpartum to reach and maintain a target blood lead (BPb) level of 35-40 microg/dL. Animals were administered succimer (n = 9) or vehicle (n = 8) over two successive 19 day succimer treatment regimens beginning at 53 and 65 weeks of age. The present study was conducted over the second chelation regimen only. Animals received a single intravenous (iv) dose of stable (204)Pb tracer (5 microg, 24.5 nmol) followed by a single oral dose of stable (206)Pb tracer (72.6 microg, 352 nmol) immediately before chelation, in order to specifically evaluate GI Pb absorption and whole-body Pb retention with treatment. We collected complete urine and fecal samples over the first 5 days and whole blood over the first 8 days of treatment for analyses of stable Pb isotopes using magnetic sector inductively-coupled plasma mass spectrometry. Results indicate that succimer significantly reduced the GI absorption of Pb (vehicle, 64.9% +/- 5.5; succimer, 37.0% +/- 5.8; mean +/- SEM). Succimer also significantly increased the urinary excretion of endogenous Pb by approximately 4-fold over the vehicle treatment, while endogenous fecal Pb excretion was decreased by approximately 33%. Finally, although succimer reduced the whole-body retention of endogenous Pb by approximately 10% compared to vehicle, the majority (77%) of the administered internal dose of Pb tracer was retained in the body when assessed after 5 days of treatment. These data do not support the concern that succimer treatment increases GI Pb absorption.

Beginning on Day 8 postpartum, lead acetate was administered to female rhesus monkeys (n=48). Their blood lead levels rose to 35-40 microg/dl (the level maintained for the duration of the study period) by 12 weeks of age. Weekly, these lead-exposed monkeys and their controls (n=23) were placed in a partially enclosed space from the second postnatal week until they escaped three times or were 26 weeks old. The lead-exposed monkeys exhibited more fear, were more likely to be agitated, and climbed more frequently during the first testing session. In subsequent sessions, they more frequently explored the periphery of the test area than the controls. The lead-exposed monkeys also tended to escape sooner although that trend did not consistently reach the.05 level of significance. The increased activity and agitation of the lead-exposed monkeys is suggestive of deficits reported in human children with high blood lead levels.

The extent to which succimer (2,3-dimercaptosuccinic acid, DMSA) chelation reduces target organ lead (Pb) levels, including the skeleton, relative to the cessation of Pb exposure is a primary consideration in evaluating its efficacy for reducing toxicity in children. Here, we utilized a rhesus monkey model of childhood Pb exposure and a sensitive stable (204)Pb isotope tracer methodology to determine the efficacy of succimer for reducing Pb in blood, liver, and skeletal tissues from chronic (>/=1 year) versus short-term (3-4 days) Pb exposures. Specific attention was paid to the efficacy of succimer treatment compared to the cessation of Pb exposure. Infant rhesus monkeys (n = 48) were exposed to Pb daily for 1 year or >1 year postpartum to reach and maintain a target blood Pb level of 35-40 microg/dL. Two successive 19-day succimer treatment regimens were administered at 53 and 65 weeks of age (30 mg/kg/day x 5 days followed by 20 mg/kg/day x 14 days). Blood was collected over the course of treatment, and liver and bone biopsy samples were collected on days 0, 5, and 20, relative to the start of treatment (day 0). Complete 24-h urine collections were conducted over the course of treatment. Results of the first chelation indicate that a single regimen of succimer treatment led to significant reductions in blood and liver Pb levels, relative to the placebo group. However, the cessation of Pb exposure alone (i.e., placebo) also led to significant reductions in blood and liver compared to pretreatment levels. Neither succimer nor the cessation of Pb exposure had a significant impact on bone lead levels. Blood Pb levels in the succimer-treated group rebounded within 5 days after treatment ended, becoming comparable with levels in the placebo group from that point on. Results from the second chelation indicate that succimer treatment is essentially equally efficacious in reducing blood Pb at moderate (20 microg/dL) levels where exposures ended >3 months previously and more elevated (40-50 microg/dL) levels where exposures ended just prior to treatment, relative to the placebo treatment. Finally, similar overall outcomes were observed for tissue Pb from recent exposures (i.e., (204)Pb tracer levels), indicating little or no apparent difference in the chelation of Pb from recent (3-4 days) versus long-term exposures. These data demonstrate that succimer does not reduce skeletal Pb levels, and they show that the efficacy of succimer for reducing blood Pb levels does not persist beyond the completion of treatment due to posttreatment rebounds in blood Pb from endogenous sources. They also demonstrate the relative benefit of eliminating Pb exposures, which serves to underscore the importance of primary prevention of Pb exposure. The extent to which these data reflect the efficacy of succimer for reducing neurocognitive impairment is not yet known, although those data are forthcoming., (Copyright 2000 Academic Press.)

Succimer is considered to be a safe and effective treatment for lead (Pb) poisoning, since it reduces body Pb levels without an apparent diuresis of other essential elements. However, while existing clinical data indicate that succimer does not significantly increase the excretion of non-target elements, those studies have also reported a wide range of outcomes. Therefore, we investigated whether succimer treatment measurably increased the urinary excretion of essential elements in a primate model of childhood Pb exposure. Infant rhesus monkeys (Macaca mulatta) were exposed to Pb from birth through one year of age, and presented blood Pb levels of approximately 40-50 microg/dL at the start of treatment. Subsequently, they were treated with succimer (30 mg/kg/day x 5 days followed by 20 mg/kg/day x 14 days, n = 15) or vehicle (n = 14) for 19 days. Complete urine samples were collected over the first 5 days of treatment, and were analyzed for levels of calcium (Ca), cobalt (Co), copper (Cu), iron (Fe), lead (Pb), magnesium (Mg), manganese (Mn), nickel (Ni), and zinc (Zn), using trace metal-clean techniques and magnetic sector-ICP-MS. Succimer treatment significantly (p < 0.05) reduced blood Pb levels when compared to the vehicle group over the treatment period, and concomitantly produced a significant >4-fold increase in urinary Pb excretion. Succimer treatment also significantly (p < 0.05, multivariate ANOVA) increased the urinary excretion of essential elements, but only when the cumulative total excretion over treatment days 1-5 for all elements were considered. None of these relative increases reached statistical significance for any particular element x day, although increases in Zn (day 3) excretion were only marginally non-significant (0.1 > p > 0.05). Multivariate analyses of a subset of elements (Cu, Fe, Mn, Zn) similarly indicated no significant effect of succimer treatment overall, although the urinary excretion of Mn was significantly increased on day 3 of treatment. Collectively, these data indicate that succimer does contribute to an increase in the urinary excretion of essential elements, although not significantly for any single element considered here. This may be important in Pb-exposed children, who can possess reduced trace element reserves due to nutritional deficiencies.

The purpose of this study was to compare multifrequency tympanometry and otoacoustic emissions (OAEs) in rhesus monkeys (Macaca mulatta) and humans. Tympanometry and OAEs can be recorded efficiently in Macaca mulatta to assess peripheral auditory function with results comparable to those in humans. Differences include (1) greater admittances and conductances in humans from 226 to 630 Hz, the frequency range validly assessed; (2) larger amplitude transient evoked OAEs (TEOAEs) and noise levels in humans; (3) larger amplitude monkey 2f(1)-f(2) distortion product OAEs (DPOAES) (f(2)s>2 kHz); (4) more prominent DPOAEs other than 2f(1)-f(2) in monkeys; (5) more narrowly tuned human f(2)/f(1) X 2f(1)-f(2) amplitude functions at the lower frequencies tested; and (6) lower 2f(1)-f(2) DPOAE thresholds at f(2)=0.5 kHz and > or = 8 kHz in monkeys.

The extent to which succimer (meso-2,3-dimercaptosuccinic acid [DMSA], Chemet) reduces brain lead (Pb) levels may be a primary consideration in evaluating its efficacy for reducing neurotoxicity. Clinical research in this area has been hampered by the need to use blood Pb levels as the index of treatment efficacy, despite the fact that brain Pb level is the exposure parameter of greater relevance to cognitive outcomes. Here, a nonhuman primate model of human Pb exposure was used to determine: (1) The efficacy of oral succimer for reducing brain Pb derived from chronic or recent exposures, and (2) The extent to which blood Pb levels reflect brain Pb prior to and following chelation. Adult rhesus monkeys were chronically exposed to Pb orally for 5 weeks to reach and maintain a target blood Pb level of 35-40 microg/dL. Chelation of Pb from recent exposures was assessed using a stable (204)Pb isotope tracer administered over 4 days prior to treatment. Immediately prior to chelation, a prefrontal cortex (PFC) biopsy was collected to determine pretreatment brain Pb levels. Subsequently, monkeys were assigned to vehicle (n = 5) or succimer (n = 6, 30 mg/kg/day x 5 days followed by 20 mg/kg/day x 14 days) groups. Blood and brain PFC, frontal lobe (FL), hippocampus (H), and striatum (S) were analyzed for total Pb and (204)Pb tracer concentrations by magnetic sector inductively coupled plasma-mass spectrometry. There were no measurable differences in brain Pb concentrations between the succimer and vehicle groups, indicating that succimer treatment was not efficacious in reducing brain Pb levels. In contrast, the cessation of Pb exposure significantly reduced brain (PFC) Pb ( approximately 34%) when compared to pretreatment levels (succimer and vehicle groups). Pb concentrations also varied among brain regions (PFC > FL approximately H > S). Finally, pretreatment PFC Pb concentrations were significantly correlated with the integrated blood Pb level (AUC) over the Pb exposure period, but not with the single pretreatment blood Pb collected concurrently with the PFC biopsy. Following treatment, blood Pb levels correlated only with Pb in the PFC, and not the other brain regions measured (FL, H, S). These data indicate that, under the conditions of this study, succimer treatment did not reduce brain Pb levels beyond the cessation of Pb exposure alone. Moreover, a single blood Pb measurement may be a poor predictor of brain Pb levels, reflecting limitations in the use of blood Pb level as an indicator of treatment efficacy., (Copyright 1999 Academic Press.)

Effects of lead exposure on behavioral development during the first month of postnatal life were examined in rhesus monkeys using a multi-item assessment scale developed for the evaluation of neonatal rhesus monkeys. Lead was administered daily beginning at day 8 postpartum at levels that produced blood lead levels of about 20 microg/dl by week 4 (n = 48); controls were treated identically but given vehicle only (n = 24). All monkeys were tested once a week for the first 4 weeks postpartum. The first principal component explained a substantial portion of the variance and was relatively consistent across ages for both groups. Analyses of the individual items and of both conceptually derived and empirically defined summary scores yielded no significant effects of lead. Furthermore, there were no systematic relationships between blood lead level and performance on the test. Correlation coefficients indicated more similarity across age for control monkeys than for lead-exposed monkeys suggesting that continuity of development, as measured by this test, was disrupted by lead. The relationship between outcome on these early assessments and later behavior will be explored in subsequent studies of these monkeys.

Distortion product otoacoustic emission (DPOAE), auditory brainstem evoked response (ABR), and behavioral thresholds were recorded in a group of 15 adult rhesus monkeys with normal auditory function. DPOAE thresholds were recorded with stimulus parameters selected to maximize signal-to-noise ratio. Additional averaging at the lowest frequencies ensured comparable noise levels across frequencies. DPOAE thresholds decreased with increasing frequency (f(2)=0.5-16 kHz) and at 16 kHz were close to 0 dB SPL. ABR thresholds were best from 1 through 16 kHz (32-38 dB peSPL); higher at 0.5 (45 dB peSPL), 24 (39 dB peSPL), and 30 kHz (49 dB peSPL). At all levels including threshold, the early ABR waves (II and I) were more prominent at the high frequencies while the later waves (IV and V) were more prominent at the low frequencies. The behavioral thresholds recorded were similar to those reported by other researchers although elevated by about 10 dB presumably because of the complexity of the threshold task. DPOAE and ABR thresholds can be reliably and efficiently recorded in the rhesus monkey and provide information concerning site of processing in the auditory pathway not directly available from behavioral data.

During the past two years, the National Institutes of Health have made significant changes in the review process for investigator-initiated research grant applications in neurotoxicology. First, study sections that formerly dealt with toxicology and alcohol, respectively, have been merged. Neurotoxicology grant applications are now reviewed by ALTX-3, a study section in which the majority of members have expertise in the neuronal, biochemical or behavioral effects of alcohol, but usually not other neurotoxicants. Second, the NIH has instituted new review criteria, in which significance, approach, innovation, investigator expertise, and research environment must all be explicitly addressed by the reviews. In this article, past and present members of the ALTX-3 study section describe the NIH review process, with emphasis on how neurotoxicology applications are handled, and provide guidelines for preparing competitive applications.

Auditory event related potentials were recorded from neonatal, 3-month, and 3-year old rhesus monkeys. Auditory brainstem evoked responses (ABRs) were reliably recorded at all ages. ABR latencies decreased with age. Age effects were greater the more centrally generated the wave. Wave I amplitude decreased with age, Wave II increased, and Wave IV remained about the same. Stimulus rate effects were greater in neonates than older monkeys. Stimulus frequency also affected the ABR, but not differentially as a function of age. Recording montage had a significant effect on the recorded waveform. Wave I tended to be larger in amplitude in horizontal recordings and front-back recordings, while the later waves were relatively more prominent in more vertical montages. Middle latency evoked responses and late potentials were less reliably recorded than the ABR. Their reproducibility improved with age. Auditory event related potentials are promising measures of auditory function for research requiring nonhuman primate models of the developing human.

A geriatric rhesus monkey (Macaca mulatta) population, previously exposed to lead, was investigated using 109Cd K X-ray fluorescence (K XRF) to determine whether metabolism of lead in bone was similar to that in human populations. The accumulation rate of lead into the tibia in this group of monkeys was determined to be 0.10-0.13 micrograms Pb (g bone mineral)-1 (microgram dl-1 year)-1, which compares well with human data, where the rate has been found to be 0.05-0.10 microgram Pb (g bone mineral)-1 (microgram dl-1 year)-1. In addition, bone lead changes over a 10-month time period were investigated, but no statistically significant difference was found. A halflife for lead in "bone" was calculated by fitting a single exponential model to serial blood lead data; the mean half-life of lead in bone was found to be 3.0 +/- 1.0 years. Both endogenous and exogenous lead exposure were found to be low at the present time, 10 years after cessation of lead intake. It is concluded that rhesus monkeys are an extremely good animal model of human bone lead metabolism and, in addition, that further research is needed to provide a more complete understanding of lead metabolism in geriatric populations.

Auditory functioning was assessed in two groups of adult rhesus monkeys (11 years of age). One (n = 11) received modest exposure to lead early in life and the other (n = 8) served as controls and did not receive any lead supplementation. Two lead-exposed monkeys had abnormal distortion product otoacoustic emissions (DPEs) and smaller amplitude or absent evoked potentials. These monkeys had abnormal distortion product otoacoustic emission (DPEs) and smaller amplitude or absent evoked potentials. These monkeys had the highest blood levels recorded in their respective groups. For the remaining lead-exposed monkeys there was little difference between their DPEs and the DPEs of the control monkeys with one exception. DPE amplitudes of the control monkeys increased more rapidly as a function of stimulus level than those of the lead-exposed monkeys at most frequencies. There was also a significant but modest effect of lead exposure on the auditory brain stem evoked responses (ABRs) of these lead-exposed monkeys. There was no apparent effect on the middle latency evoked responses (MLRs), although that result could be due to the relatively greater variability of the MLR.

Distortion product otoacoustic emissions (DPOAEs) were compared in eight rhesus monkeys (Macaca mulatta) and eight normal hearing humans. DPOAEs were recorded in three conditions. In the first condition, DPOAEgrams were generated for monkeys and humans from approximately f2 = 0.5-20 kHz. Monkeys had larger amplitude DPOAEs at all frequencies except around f2 = 1 kHz. In the second condition, DPOAE amplitudes increased and then decreased as the separation between the primaries increased. These functions were similar in the two species except at the lowest frequencies assessed. In the third condition, the levels of the primaries were varied independently. Monkeys had steeper input/output (I/O) functions than humans. The slopes of DPOAE I/O functions increased with frequency in both species. When the levels of both primaries were increased simultaneously, DPOAE I/O functions were well described by power functions throughout the intensity range assessed (from threshold to 65 dB SPL). Monkey I/O functions tended to be expansive power functions at all but the lowest frequencies, while human I/O functions tended to be compressive power functions except at the highest frequencies assessed. Other differences in I/O functions f2 = 8 kHz may indicate species specific differences at high (for human) frequencies.

Early (ABRs) and middle (MLRs) surface-recorded auditory evoked potentials were compared in eight adult monkeys (Macaca mulatta) and eight adult humans. Responses whose probable generators were the cochlear nucleus and lateral lemniscus were of shorter latency and larger amplitude in monkeys. Relative to humans, ABR response latencies in monkeys were less affected by stimulus intensity, stimulus rate, and masker level. In contrast, monkey amplitudes were relatively more affected by those same stimulus parameters. The most prominent MLR wave was longer in latency and greater in amplitude in humans than the homologous wave in monkeys. The reduction in amplitude of that wave with increasing rate was greater for humans than monkeys. Temporal interactions (the effect of prior stimuli on the response to current stimulation) were investigated from a non-linear systems identification framework using maximum length sequences (MLSs). Both monkey and human auditory systems were second and probably third-order systems at the levels assessed. As the separations between the stimulus pulses decreased, evidence for temporal interactions became more prominent, reached a maximum, and then decreased with further decreases in stimulus pulse separation. At the highest stimulus rates presented, variations in temporal spacing among stimuli had less of an effect on monkey than human evoked responses.

Lead-binding proteins have previously been isolated from rat and human target tissues. These molecules have shown to possess molecular masses in the general range of 10,000-30,000 daltons. The proteins are acidic in nature and rich in aspartic and glutamic amino acid residues. The molecules in rodents appear to play several important roles in mediating the low dose toxicity of lead in the kidney and brain. Preliminary studies presented in this report indicate that monkeys also possess similar proteins in the kidney and brain, thus providing a biochemical "bridge" in a non-human primate between rodent models and humans. Further, the excretion of these molecules into the urine of rodents increases with lead exposure, suggesting that may also prove useful as biomarkers of lead exposure in humans and monkeys once the dose-range and mechanism(s) of this phenomenon are further defined. Such studies should provide valuable risk assessment information for determining why individuals vary in their susceptibility to lead toxicity.

Infant rhesus monkeys ingested 0 or 1.0 mg/kg lead acetate daily from birth to one year postpartum in dietary milk. Half the monkeys in each group were offered milk ad lib, and half were given restricted quantities. Chow was available ad lib to all monkeys. Groups of 4 monkeys interacted for 1.5 h/day, 5 days/week beginning at approximately 2 months of age. The social sessions were moved to a larger arena at about 9 months postpartum. Ongoing behavior was observed during social sessions twice weekly beginning at about 3 months of age for 28 weeks, and again beginning at about 16 months of age for 11 weeks. Play behaviors were particularly susceptible to lead; social play was more severely disrupted than nonsocial play. Lead suppressed play in both test environments during the first year postpartum while self-stimulation and fearful behaviors increased. Lead-associated alterations in behavior were still present several months following termination of lead intake. Restriction of milk resulted in increased chow consumption but had little impact on behavior. Effects of lead may have been more profound in monkeys maintained on the restricted milk diet than in monkeys given milk ad lib.

Swiss/ICR mice were tested to determine whether the volatile ether anesthetic, enflurane, causes induction of anesthetic defluorination and organ toxicity. Mice were exposed in utero and postnatally to 0.01, 0.1 and 1.0 volumes percent enflurane vapor. Body weight was measured at frequent intervals throughout the experiment. Animals were sacrificed at 73 days of age and liver microsomal cytochrome P-450 content and the rate of defluorination of enflurane, isoflurane, methoxyflurane ans sevoflurane were determined. In addition, the liver, kidney and testis were weighed and examined histologically for drug induced damage. The maximum tolerated dose of enflurane delivered over a twelve week period was determined to be 0.5 volumes percent for four hours a day, five days a week. Even at this high dose there was no evidence in either sex of liver, kidney or testicular damage. Following enflurane exposure, neither the liver microsomal cytochrome P-450 content nor the rate of anesthetic defluorination was increased. The rate of in vitro inorganic fluoride production per unit time was greatest for methoxyflurane, and approximately equal for enflurane, isoflurane and sevoflurane. Since there was no evidence of enzyme induction or specific organ toxicity, it was concluded that enflurane is a comparatively nontoxic volatile anesthetic under conditions of this study.

Monkeys exposed to PCB mixtures during gestation and lactation were tested on two-choice discrimination-reversal learning (DR). In Experiment 1, offspring of mothers fed 1.0 ppm Aroclor 1248, and offspring born 1.5 years after maternal exposure to 2.5 ppm Aroclor 1248 ended did not differ from controls on spatial, color or shape DR problems. In Experiment 2, offspring of mothers fed 0.25 or 1.0 ppm Aroclor 1016 and offspring born 3 years after maternal exposure to 2.5 ppm Aroclor 1248 ended were tested on the same spatial, color and shape problems, but a spatial problem with color and shape as irrelevant cues was inserted after the initial spatial problem. Performance of the high dose Aroclor 1016 offspring was impaired on the initial spatial problem, and facilitated on the shape problem. Performance of the Aroclor 1248 postexposure offspring was facilitated on the shape problem. This apparently facilitatory effect may represent a failure of PCB-exposed monkeys to learn the irrelevancy of the shape cue when it was initially presented.

Adult, female rhesus monkeys ingested lead daily for three 1-year exposures over a 5-year period followed by chronic lead intake for 3 additional, consecutive years. Lead was administered as lead acetate in the drinking water at levels producing average circulating concentrations of lead between 44 and 89 micrograms/100 ml and zinc protoporphyrin concentrations between 87 and 105 micrograms/100 ml. The monkeys were without overt signs of lead toxicity at all times; i.e., appetite, body weight, and hematocrit levels were normal. Menstrual cycles were altered by lead. During the last 2 years of exposure, the lead-treated monkeys had less frequent cycles, longer and more variable intercycle intervals, and fewer days of vaginal bleeding than controls. These differences were not due to seasonal artifacts or differences in exposure to environmental influences such as light or diet. Further, historical data indicated that cycles were normal for the treated monkeys prior to exposure to lead and that three of four cycle characteristics remained normal during the first lead exposures. Duration of vaginal bleeding was initially attenuated by lead but returned to normal when lead intake was discontinued between exposures. In contrast, the effects of lead observed during the later years of exposure remained apparent 1 year following termination of lead ingestion. These results suggest that persistent alterations of the menstrual cycle and perhaps premature menopause resulted from prolonged exposure to lead at levels which produced no obvious signs or symptoms of toxicosis.

Categorical perception of place of articulation contrasts was evaluated in rhesus monkeys. The monkeys had been chronically exposed to subclinical levels of lead, either from conception to birth, or for approximately 6 months beginning at birth, or were never exposed to lead. Auditory evoked responses were recorded from scalp electrodes placed over left and right hemispheres during stimulus presentation. The brain responses recorded from the right hemisphere of the normal control group of monkeys discriminated between the categories of [dae] and [gae]. Categorical discriminations were also noted for monkeys exposed to lead either prenatally or postnatally. These discriminations, in contrast, were found over only the left hemisphere. In additions, postnatal exposure resulted in categorical discrimination associated with slower latency components, suggesting a less mature pattern than that obtained for prenatally exposed monkeys. Finally, the brain responses of the animals in the normal control and postnatal exposure conditions evidenced reliable within-category, as well as between-category, discriminations. These results suggest that the neurocortical mechanisms associated with categorical perception of place information may differ between human and nonhuman primates and that early exposure to lead alters these processes.

Exposure to lead in the workplace or home environment has been implicated as a cause of decreased fertility in women. In a previous study, as part of our effort to determine effects of lead in primates, female rhesus monkeys were exposed to lead acetate in drinking water (n = 10) or provided water with no added lead (n = 7) for 33 mo. Lead was administered at levels between 2 and 8 mg/kg/day, with doses adjusted to keep blood lead values near a target of 70 micrograms/dl (observed mean +/- SEM = 68.9 +/- 6.54 micrograms/dl). Blood lead concentrations in control animals were less than 10 micrograms/dl. No significant differences were detected between control and experimental animals in body weight, hematocrit, or general health. Female monkeys receiving lead exhibited longer and more variable menstrual cycles and shorter menstrual flow. In the present study, circulating amounts of progesterone (P4) were determined to evaluate luteal function during the final 7 mo of treatment with lead. Several characteristics were altered as a result of lead treatment: circulating amounts of P4 were reduced as indicated by relative units of area under the concentration-time curve, maximal amounts of P4 were reduced, and P4 levels were greater than 1 ng/ml on fewer days. There were no significant differences between groups in mean percent of anovulatory cycles. Therefore, although chronic treatment with the levels of lead used in this study did not prevent ovulation, luteal function was suppressed. These results extend previous observations of adverse effects of lead on ovarian activity and fertility in monkeys.

Motion projections (pictures) simulating a horizontal array of vertical lines rotating in depth about its central vertical line were observed by 24 college students who rotated a crank handle in the direction of apparent rotation. All displays incorporated contradictory motion perspective: Whereas the perspective transformation in the vertical (y) dimension stimulated one direction of rotation, the transformation in the horizontal (x) dimension simulated the opposite direction. The amount of perspective in each dimension was varied independently of the other by varying the projection ratio used for each dimension. We used the same five ratios for each dimension, combining them factorially to generate the 25 displays. Analysis of variance of the duration of crank turning which agreed with y-axis information yielded main effects of both x and y projection ratios but no interaction, revealing that x- and y-axis motion perspectives mediate kinetic depth effects which are functionally independent.

Categorical perception of voicing contrasts was evaluated in rhesus monkeys. The monkeys had been chronically exposed to subclinical levels of lead either from conception to birth, or for approximately 6 months postnatally beginning at birth, or were never exposed to lead. Auditory evoked responses were recorded at 1 year of age from scalp electrodes placed over the left and right hemispheres during stimulus presentation. A late component of the brain responses recorded from the right temporal region of all monkeys discriminated between stimuli in a categorical manner. This pattern of responses was noted to be similar to that previously reported for humans. Categorical discriminations were also noted earlier in the waveforms for control monkeys and for monkeys exposed to lead prenatally, although this discrimination pattern shifted to the left hemisphere of the latter group. No such effects were noted for monkeys exposed to lead postnatally. These results suggest that the neurocortical mechanisms associated with categorical perception for voicing information may be similar across human and nonhuman primates. However, early exposure to lead appears to alter these processes.