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.

BackgroundTactile defensiveness in children is associated with difficult social relations, emotional dysregulation, and inattention. However, there are no studies of lead exposure and tactile defensiveness in children or animals in spite of the fact that lead exposure is also associated with inattention and emotional dysregulation.ObjectivesIn this study we tested whether lead exposure induces tactile defensiveness in rhesus monkeys.MethodsWe tested 61 monkeys from a 3 (no lead, 1-year lead, 2-year lead) × 2 (succimer chelation or not) factorial experiment for tactile defensiveness at 4 years of age. Lead-treated monkeys had been orally administered lead in a daily milk solution from 8 days of life to either 1 or 2 years of age to produce blood lead levels of 35–40 mg/dL. Succimer chelation therapy or placebo was administered at 1 year of age. We measured tactile defensiveness using six repeated trials of each of three textures as a swipe to the cheek and neck.ResultsLead-exposed monkeys showed higher negative responses to repeated tactile stimulation compared with controls. Blood lead during the first 3 months of life was positively correlated with the negative response on the tactile defensiveness test. There was an interaction of lead exposure × succimer chelation × trials, but it is not clear that succimer chelation was beneficial with respect to tactile defensiveness.ConclusionsThis is the first report to implicate lead as a potential cause of tactile defensiveness. Research should examine whether lead exposure is associated with tactile defensiveness in children.

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.

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 μmol/L (35–40 μg/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.

Thirty-one female rhesus monkeys were randomly assigned to three lead exposure conditions (none, birth to 1 year, and birth to 2 years). Blood lead levels were maintained at 35–40 μg/dl beginning shortly after birth and continuing for 1 or 2 years postnatally. Auditory function was assessed in these monkeys at least 1 year after exposure to lead. The outcome measures included tympanometry to assess middle ear function, otoacoustic emissions (OAEs) to assess cochlear function, and auditory brainstem-evoked responses (ABRs) to assess the auditory nerve and brainstem pathways. There were no significant differences among the three experimental groups for any of the tympanometric variables measured suggesting no effect of lead exposure on middle ear function. Suprathreshold and threshold distortion product OAEs (DPOAEs) were comparable among the three groups. Finally, the auditory-evoked response at levels from the auditory nerve to the cerebral cortex did not significantly differ as a function of lead exposure. The lead exposure in this study had little effect on auditory function.

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.

Developmental PsychobiologyVolume 38, Issue 2 p. 89-91 In memoriam: Robert W. Bell, November 22, 1931– September 16, 2000 Michael B. Hennessy, Corresponding Author Michael B. Hennessy Department of Psychology, Wright State University, Dayton, OH 45435Department of Psychology, Wright State University, Dayton, OH 45435Search for more papers by this authorNellie K. Laughlin, Nellie K. Laughlin Department of Psychology, Wright State University, Dayton, OH 45435Search for more papers by this author Michael B. Hennessy, Corresponding Author Michael B. Hennessy Department of Psychology, Wright State University, Dayton, OH 45435Department of Psychology, Wright State University, Dayton, OH 45435Search for more papers by this authorNellie K. Laughlin, Nellie K. Laughlin Department of Psychology, Wright State University, Dayton, OH 45435Search for more papers by this author First published: 05 February 2001 https://doi.org/10.1002/1098-2302(200103)38:2<89::AID-DEV1000>3.0.CO;2-VAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume38, Issue2March 2001Pages 89-91 RelatedInformation

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.

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 μg/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.

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.

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 204Pb 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 μg/dL. Two successive 19-day succimer treatment regimens were administered at 53 and 65 weeks of age (30 mg/kg/day × 5 days followed by 20 mg/kg/day × 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 μg/dL) levels where exposures ended >3 months previously and more elevated (40–50 μg/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., 204Pb 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.

The purpose of this study was to compare multifre-quency tympanometry and otoacoustic emissions (OAEs) in rhesus monkeys (Macaca mulatto) 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 2ft—f2 distortion product OAEs (DPOAES) (f2s<2 kHz); (4) more prominent DPOAEs other than 2f1-f2 in monkeys; (5) more narrowly tuned human f2/fl X 2f]-f2 amplitude functions at the lower frequencies tested; and (6) lower 2f,-f2 DPOAE thresholds at f2=0.5 kHz and ⩾ 8 kHz in monkeys.

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 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.