Chronic maternal methanol inhalation in nonhuman primates (Macaca fascicularis): reproductive performance and birth outcome

The present study was designed to characterize maternal reproductive performance and early offspring effects following exposure to methanol (MeOH) vapor in a nonhuman primate model. The two-cohort study design used 48 adult female Macaca fascicularis (24/cohort) monkeys exposed to 0, 200, 600, or 1800 ppm MeOH vapor for approximately 2.5 h/day, 7 days/week prior to breeding and throughout pregnancy. Maternal body weight measurement, clinical observations and health assessments were conducted routinely throughout the study. Menstrual cyclicity was monitored during the pre-breeding and breeding periods and timed matings were conducted with nonexposed males. Females were monitored closely during the last month of pregnancy. At birth, infant physical characteristics were measured and a newborn health assessment was conducted. Methanol exposure did not alter menstrual cycles, the number of breedings to conception or conception rate. A total of 34 live-born infants were delivered (control=8, 200 ppm=9, 600 ppm=8, 1800 ppm=9). One female each in the control and 600-ppm group delivered a stillborn infant and a cesarean section (C-section) was required to deliver a hydrocephalic infant who died in utero in the maternal 1800-ppm group. Although not statistically significant, five MeOH-exposed females were C-sectioned due to pregnancy complications such as uterine bleeding and prolonged unproductive labor. These complications were not observed in the control group. The mean length of pregnancy in the MeOH-exposed groups was significantly decreased by 6 to 8 days when compared to controls. There were no MeOH-related effects on offspring birthweight or newborn health status. The consistent reduction in length of pregnancy observed in the MeOH females may reflect a treatment effect on the fetal neuroendocrine system. Given that the fetal hypothalamic--pituitary-adrenal axis controls pregnancy length in most species, these results suggest a modest but significant effect of MeOH on the biochemical events that control the timing of birth.     

Pulmonary hyperreactivity in cynomolgus monkeys (Macaca fascicularis) from nose-only inhalation exposure to disodium hexachloroplatinate, Na2PtCl6

The pulmonary and dermal effects of exposure to Na2PtCl6 were investigated in cynomolgus monkeys (Macaca fascicularis) exposed by the nose-only inhalation and percutaneous routes. Separate inhalation exposures were performed in monkeys at 200 micrograms/m3 and 2 mg/m3 (4 hr/day, biweekly for 12 weeks), while another group of monkeys was percutaneously exposed biweekly by an open patch method. After a 2-week refractory period, serial Na2PtCl6 bronchoprovocation challenges and intradermal Na2PtCl6 sensitivity evaluations were performed. Na2PtCl6 bronchoprovocation in naive control monkeys yielded significant impairments in post-challenge pulmonary mechanics and ventilatory function. These results indicate a pharmacologic or irritant-mediated bronchoconstriction mechanism for acute exposure to this compound. When the post-challenge pulmonary function of animals exposed for the 12-week exposure regimen (across treatments) was compared to pulmonary deficits observed in control animals upon challenge, significantly greater pulmonary deficits were seen in animals exposed at the 200 micrograms/m3 concentration. Exposure at this concentration yielded significant changes in post-challenge average pulmonary flow resistance (RL) and forced expiratory volume in 0.5 sec corrected for vital capacity (FEV0.5/FVC) when compared to control monkey responses. Animals exposed by the percutaneous route or at 2 mg/m3 showed no significant post-challenge pulmonary deficits when compared to control animals. Intradermal Na2PtCl6 sensitivity was found not to be exposure related in the conditions of this experiment.     

Proposal for reference concentrations (RfC) for inhalation exposure to methanol

A tentative reference concentration (RfC) for methanol in ambient air, i.e. an exposure concentration below which adverse effects are not expected to occur, was derived from the analysis of the toxicological data available in the literature. Well-documented studies that correlate environmental levels of methanol with observed toxic effects have not been found in the literature, nor have any long-term epidemiological studies of chronic low-level occupational exposure been found. Assessment of RfC for acute inhalation exposure is based on a human study (n=26 subjects) with a 'tentative' NOAEL of 262 mg/m(3). The calculated RfC for 1 h exposure is 104.8 mg/m(3). The RfC is given a low confidence rating as there was only one methanol concentration used. A well designed study on monkeys served as the basis for the assessment of RfC for chronic inhalation exposure. In this study, 13.1 and 131 mg/m(3) were considered as NOAEL and LOAEL, respectively. The calculated RfC is 0.38 mg/m(3). The overall database is weak, lacking data on reproductive and developmental endpoints in human or non-human primates. Nevertheless, the RfC is given a medium confidence rating because of the strength of the principal study.     

Chronic cadmium exposure during pregnancy in the mouse: influence of exposure levels on fetal and maternal uptake

The uptake and distribution of orally administered cadmium-109 was studied in pregnant mice. Female outbred QS mice were given cadmium (Cd) supplemented drinking water for 1 mo before pregnancy and for the duration of pregnancy. The water contained either 0.0015 ppm Cd, 0.24 ppm Cd, or 40 ppm Cd. For the duration of pregnancy, 1.48 micrograms Cd/l (0.0015 ppm) in each solution was in the form of 109Cd (1 mCi/l). Control mice were given distilled/deionized water. On the day before term the mice were killed and a variety of adult and fetal tissues were examined in a gamma counter to determine their 109Cd concentrations. For each group the 109Cd concentration was highest in the maternal gastrointestinal tract, liver, and kidneys and lowest in the central nervous system (CNS) and blood. In general, the 109Cd concentrations in each organ were similar for each group of mice and were therefore independent of the overall oral Cd dose. A notable exception was the lower level in the duodenum in the 40 ppm group. In the fetal unit the chorioallantoic placenta contained the highest concentration of 109Cd. Concentrations in the fetuses were very low, comparable to those in the adult CNS. The 109Cd levels in the fetuses from group A were about fivefold greater than those of the fetuses from group C. There was no statistically significant evidence of specific localization in the fetal brain, kidney, or liver.     

Evaluation of the onset and duration of response to cold air inhalation challenge in cynomolgus monkeys (Macaca fascicularis)

Cold air inhalation challenge (CAIC) for the evaluation of bronchial reactivity has been proposed as a physical agent alternative to chemical agent challenges (methacholine or histamine), especially suitable for the occupational environment. The present investigation describes and evaluates a method for performing cold air inhalation challenge in Cynomolgus monkeys (Macaca fascicularis), a species shown to be useful in animal modeling studies of occupational asthma. Six adult male anesthetized monkeys were ventilated by changes in external pressure while breathing cold air (-25 degrees C to -30 degrees C). Pulmonary function testing was performed at 10, 25, 40 and 55 min post-challenge. Significant increases (P less than 0.05) in average pulmonary flow resistance (RL) and decreases in dynamic compliance (CL dyn) were observed, with maximum impairment occurring at 25 min post-challenge, with a trend towards a return to baseline values at 55 min post-challenge. Peak expiratory flow rate (PEFR), forced expiratory volume in 0.5 s/forced vital capacity (FEV0.5/FVC) and forced expiratory flow at 50% forced vital capacity (FEF50) showed the same general pattern of reduction as seen with RL; however, these results were not statistically significant, most probably owing to individual monkey variability and the small number of monkeys (N = 6) used. A repeat challenge at 25 min after a primary challenge yielded increased RL in one monkey, suggesting that no absolute refractory period is present from CAIC. Results of these studies demonstrate that CAIC causes bronchoconstriction in monkeys and may be useful in further animal modeling studies designed to determine the asthmogenic/airway irritant potential of occupational toxicants.     

Chronic colitis in Macaca fascicularis: similarities with chronic colitis in humans

In recent years, a substantial number of macaques have died at the Southwest Foundation for Biomedical Research, USA, following protracted intractable diarrhea. The diarrhea could last for up to two years and occurred in infant, juvenile or young adult animals. The histopathological diagnosis at autopsy was chronic colitis. The histopathological subtype of chronic colitis is here assessed in a relatively large number of colonic specimens obtained at autopsy (n = 90). The colonic mucosa was well preserved for histological examination in 83 of the 90 macaques. At review, various histological phenotypes of chronic colitis were found. Chronic lymphocytic-plasmacytic colitis occurred in 78.3% (65 out of 83), chronic ulcerative colitis in 20.5% (17 out of 83) and Crohn's colitis in 1.2% (1 out of 83). In macaques, some histological phenotypes of chronic colitis (ulcerative and Crohn's colitis) closely mimic chronic colitis in humans. The awareness that chronic colitis in macaques is not one disease but a series of chronic inflammatory changes, with common clinical symptoms and similar gross appearances, may lead to the correct histological diagnosis of the subtype of the disease.     

Effects of maternal exposure to di(2-ethylhexyl)phthalate (DEHP) during pregnancy on susceptibility to neonatal asthma

Di(2-ethylhexyl) phthalate (DEHP) is used as a plasticizer and is widely dispersed in the environment. In this study, we investigated the effects of maternal exposure to DEHP during pregnancy on neonatal asthma susceptibility using a murine model of asthma induced by ovalbumin (OVA). Pregnant BALB/c mice received DEHP from gestation day 13 to lactation day 21. Their offspring were sensitized on postnatal days (PNDs) 9 and 15 by intraperitoneal injection of 0.5 μg OVA with 200 μg aluminum hydroxide. On PNDs 22, 23 and 24, live pups received an airway challenge of OVA for 30 min. Offspring from pregnant mice that received DEHP showed reductions in inflammatory cell count, interleukin (IL)-4, IL-13, and eotaxin in their bronchoalveolar lavage fluid and in total immunoglobulin E and OVA-specific IgE in their plasma compared with offspring from pregnant mice that did not receive DEHP treatment. These results were consistent with histological analysis and immunoblotting. Maternal exposure to DEHP reduces airway inflammation and mucus production in offspring, with a decrease in inducible nitric oxide synthase (iNOS) in the lung tissue. This study suggests that maternal exposure to DEHP during pregnancy reduces asthmatic responses induced by OVA challenge in offspring. These effects were considered to be closely related to the suppression of Th2 immune responses and iNOS expression.     

Alcohol self-administration in monkeys (Macaca radiata): the effects of prior alcohol exposure.

Responding by 4 monkeys was maintained under a fixed ratio 10 (FR 10) schedule for either food, intravenous sucrose or alcohol. The 20 hr sessions were divided so that food was available during hours 1, 6, 11, 16 and alcohol or sucrose during hours 2-5, 7-10, 12-15, and 17-20. All animals failed to maintain responding for isocaloric sucrose but continued to respond for food during those sessions. Responding under alcohol conditions was positively accelerated in 2 animals that were not previously exposed to alcohol, whereas prior exposure to alcohol produced maximal response rates during the first alcohol test session. The effects of alcohol in all monkeys were to suppress responding maintained by food and this suppression could not be produced with programmed infusions of isocaloric sucrose.     

Kinetics of methyl mercury in blood and brain during chronic exposure in the monkey Macaca fascicularis

The disposition parameters derived from a compartmental model kinetic analysis of blood Hg levels in nonpregnant, adult female Macaca fascicularis given daily doses of MeHg did not vary with either dosage level (50, 70 or 90 micrograms MeHg/kg b.wt.day) or duration of exposure (up to 507 day). In contrast, blood clearance of Hg in pregnant females was dose-dependent; it being higher at the 90 micrograms MeHg/kg b.wt.day than at the lower dosage levels. Hg levels in the brain of adult fascicularis relative to blood Hg also increased at the highest level of exposure. Blood Hg half-life in neonate fascicularis was similar to half-life in their mothers (adults). Finally, the regional distribution of mercury in the brains of adult and neonate fascicularis exposed to low and intermediate levels of MeHg resembles the reported distribution of mercury in the brains of adult and neonate humans environmentally exposed to MeHg. Consequently, M. fascicularis may be an especially appropriate animal model for studying the neurotoxic mechanisms of chronic methyl mercury exposure.     

Acute trimethyltin intoxication in the monkey (Macaca fascicularis)

Adult cynomolgus monkeys were administered trimethyltin (TMT) iv in dosages ranging from 0.75 to 4.0 mg TMT/kg and observed for behavioral changes. Animals were subsequently killed for light and electron microscopic examination. TMT showed a dose-related toxicity, with high dose animals (4.0 and 3.0 mg/kg) dying within 24 hr, and low dose animals (0.75 mg/kg) surviving without morphological effects. Animals given 1.10 mg TMT/kg displayed a reproducible clinical course, characterized by tremor, hyperactivity, and ataxia which progressed to stupor and finally unconsciousness. By light microscopy, neuropathology was most pronounced in the CA-3 and CA-4 regions of Ammon's horn. Degenerating pyramidal neurons, micro- and astrogliosis, and neuronophagia were commonly observed. Mild degenerative changes were identified in amygdala, medulla, spinal cord, and Purkinje cells. The fascia dentata remained intact. Ultrastructurally, injured neurons contained accumulations of lysosomes and lysosome-like structures within perikarya and neurites. Demyelination or vascular damage was not observed. Data indicate the monkey to be highly sensitive to TMT, with morphological injury most severe in limbic structures.     

High intra-uterine exposure to infliximab following maternal anti-TNF treatment during pregnancy

Aliment Pharmacol Ther 2011; 33: 1053–1058

Summary

Background Typically, inflammatory bowel disease (IBD) patients are in their reproductive years, raising questions about safely using antitumour necrosis factor antibodies like infliximab (IFX) during pregnancy. IgG antibodies naturally cross the placenta, especially during the last trimester. To prevent foetal intra‐uterine exposure, stopping IFX treatment at gestational week 30 is recommended. However, whether this limits intra‐uterine and early postnatal IFX exposure is unestablished. Aim To determine the intra‐uterine exposure to IFX following maternal treatment with IFX. Methods Four pregnant IBD patients intentionally continued IFX during pregnancy. IFX levels were assessed in newborns’ cord blood and the mothers’ peripheral blood at delivery. The children’s development during the first 3–6 months, infections, vaccine reactions and antibody responses to vaccinations against Haemophilus influenzae type b and Pneumococcus were assessed. Results The patients stopped IFX therapy at gestational week 21, 26, 26 and 30, respectively. In three infants, therapeutic IFX levels were present in cord blood at levels of 5.5–13.7 μg/mL and were two‐ to three‐fold higher than in the peripheral blood of their mothers. During the 3‐ to 6‐month follow‐up, the children developed normally without signs of infections or allergic reactions, and had normal antibody titres after routine childhood vaccinations. Conclusion The use of IFX until gestational week 30 leads to foetal intra‐uterine exposure to IFX at levels that exceed those in the mothers’ peripheral blood. Although no short‐term complications were detected, the high IFX levels observed in newborns raise concerns about unknown effects of IFX on the developing immune system.     

Toxicological consequences of feeding PCB congeners to infant rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) monkeys.

In a study designed to minimize interspecies extrapolation of toxicological data, nine rhesus (Macaca mulatta) and 15 cynomolgus (M. fascicularis) day-old infant monkeys were separated from their dams following parturition and hand-reared using a liquid non-human primate formulation. The infants were randomly divided into a control and a treated group which received a mixture of polychlorinated biphenyl (PCB) congeners analogous to those found in breast milk from Canadian women. The concentration of congeners in the dosing media resulted in each infant receiving a total of 7.5 microg PCB congeners/kg body weight/day. The congeners were added either to the liquid formulation or to corn oil and administered to the back of the monkey's mouth for 20 weeks. Monthly blood and adipose specimens were obtained during the dosing period and then periodically until the monkey was necropsied or taken off test (minimum of 66 weeks on test) for congener analysis. Parameters such as body weight, formula consumption, tooth eruption, somatic measurements, haematology and serum biochemistry were monitored throughout the study. In addition, a qualitative evaluation of the absorption and depletion of the various congeners was undertaken as was an immunological evaluation. For the monitored parameters, very few differences were found to be statistically significant. For the immunological parameters, the only statistically differences found were a reduction over time for immunoglobulins M and G antibodies to sheep red blood cells (cyno, P = 0.025; rhesus, P = 0.002) and a treatment-related reduction in the levels of the HLA-DR cell surface marker (mean percent, P = 0.016; absolute levels, P = 0.027). There were some qualitative differences regarding absorption and depletion rates for the various congeners, but it could not be definitely ascertained whether these differences were due to species differences or dosing mode. However, statistically significant differences were found for treatment (P = 0.0293) as well as for species and vehicle regarding the concentration of PCB in blood (species;--P = 0.0399; treatment--P = 0.0001) and adipose tissue (species--P = 0.0489; treatment--P = 0.0001).     

Chronic exposure to the opioid growth factor, [Met5]-enkephalin, during pregnancy: maternal and preweaning effects.

The opioid peptide, [Met(5)]-enkephalin (termed opioid growth factor, OGF), is an autocrine growth factor that serves as a constitutively active inhibitory agent. OGF crosses the placenta and depresses DNA synthesis in the fetus. The role of OGF in pregnancy and parturition, and the influence exerted on prenatal and neonatal features of the offspring, were studied in rats. Females received daily injections of 10 mg/kg OGF throughout gestation; all offspring were cross-fostered to lactating noninjected dams at birth. No effects on the length of gestation, course of pregnancy, behavior of the pregnant dam, maternal weight gain, or food and water intake throughout gestation were recorded in OGF-treated mothers. Moreover, nociceptive response in these females was not altered by chronic OGF exposure, and no signs of physical dependence or withdrawal could be observed following a challenge by the opioid antagonist naloxone. Litter size and the number of live births per litter of OGF-treated mothers were reduced by 25% from control subjects and a fourfold increase in stillborns was noted for mothers receiving OGF compared to control levels. Histopathologic analysis confirmed the stillborns to have died in utero. OGF-exposed neonates were normal in body weight and crown-to-rump length, but these pups were observed to be lethargic and cyanotic, and had subnormal weights of many organs. Body weights of 10-, 15-, and 21-day-old OGF-exposed rats were reduced 11-27% from control levels. Wet and dry organ weights of the rats maternally subjected to OGF were decreased from control values in six of the eight organs evaluated at 10 days. At weaning, some organs were subnormal in weight. These data lead us to hypothesize that a native opioid peptide-OGF-is integral to certain aspects of maternal, neonatal, and postnatal well-being, and that disruptions in this opioid peptide have serious repercussions on the course of pregnancy and fetal outcome.     

Effects of Chronic Caffeine Consumption in Pregnant Monkeys (Macaca fascicularis) on Blood and Urine Clinical Chemistry Parameters

Pregnancy requires a variety of physiological adaptations tocreate an environment for the optimal development of the fetus.The widespread consumption of the methylxanthines especiallycaffeine and to a lesser extent theophylline by pregnant womensuggests that it is important to determine whether these methylxanthinesmay influence maternal physiology during pregnancy. Forty femalemonkeys (Macaca fascicularis), randomly divided into three groups,were exposed to caffeine in their drinking water (0, 0.15, or0.35 mg/ml) before, during, and after pregnancy. This exposureresulted in a dose-related increase in reproductive failurein the form of stillbirths, miscarriages, and decreased maternalweight gain. Blood and 24-hr urine samples were collected every2 weeks for clinical chemistry analysis. There were a numberof both pregnancy-related changes and treatment-related effectson the clinical chemistry measures. As expected, serum cholesteroland triglyceride levels declined during pregnancy for all dosegroups but there were no treatment-related effects. Serum andurine creatinine levels were increased in both treated groups.Serum glucose levels, which usually decline during pregnancy,remained elevated in the high-dose group. Serum estrogen levelsin the high-dose groups were depressed compared to those ofthe other two groups. These changes indicate that elevated serumlevels of caffeine and its metabolites, particularly theophylline,may influence maternal physiology during pregnancy in the monkey.     

Toxicity of 8-methoxypsoralen in cynomolgous monkeys (Macaca fascicularis)

Male and female cynomolgous monkeys were administered 0, 2, 6 or 18 mg/kg 8-methoxypsoralen (8-MOP) 3 times a week orally for 26 consecutive weeks. Dose-dependent emesis was the most sensitive indicator of 8-MOP toxicity. The lowest dose to elicit emesis was 3 x 6 mg/kg/week of 8-MOP. Among the histological findings proliferation of Kupffer cells was the only recurring observation. However, these finding as well as some hematological and serum electrolyte changes lacked a dose-response relationship. In the highest dosage group one female monkey was found in moribund condition on the 39th day of the study and was killed. Histopathological evidence indicated beginning shock as the cause of the rapidly deteriorating health of the monkey. Similar to effects in man and rats, 8-MOP displayed nonlinear pharmacokinetics in the cynomolgous monkey, saturation occurring between 3 x 2 and 3 x 6 mg/kg/week. Increased clearance of 8-MOP in the lowest dosage group after 26 test weeks was attributed to a combination of enzyme induction and saturable first pass effect. Since the plasma profile of 8-MOP at the lowest dose (3 x 2 mg/kg/week) in cynomolgous monkeys closely resembles that in humans after therapeutic doses (0.4-0.6 mg/kg) and because of other similarities (vomiting as earliest sign of toxicity, saturable first pass effect), it is reasonable to assume that chronic toxicity of 8-MOP as defined in this study is quite predictive for man.     

Diurnal pituitary-adrenal activity during schedule-induced polydipsia of water and ethanol in cynomolgus monkeys (Macaca fascicularis)

Rationale

Intermittent delivery of an important commodity (e.g., food pellets) generates excessive behaviors as an adjunct to the schedule of reinforcement (adjunctive behaviors) that are hypothesized to be due to conflict between engaging and escaping a situation where reinforcement is delivered, but at suboptimal rates.

Objectives

This study characterized the endocrine correlates during schedule-induced polydipsia of water and ethanol using a longitudinal approach in non-human primates.

Methods

Plasma adrenocorticotropic hormone (ACTH) and cortisol were measured in samples from awake cynomolgus monkeys (Macaca fascicularis, 11 adult males) obtained at the onset, mid-day, and offset of their 12-h light cycle. The monkeys were induced to drink water and ethanol (4 %?w/v, in water) using a fixed time (FT) 300-s interval schedule of pellet delivery. The induction fluid changed every 30 sessions in the following order: water, 0.5 g/kg ethanol, 1.0 g/kg ethanol, and 1.5 g/kg ethanol. Following induction, ethanol and water were concurrently available for 22 h/day.

Results

The FT 300-s schedule gradually increased ACTH, but not cortisol, during water induction to a plateau sustained throughout ethanol induction in every monkey. Upon termination of the schedule, ACTH decreased to baseline and cortisol below baseline. Diurnal ACTH and cortisol were unrelated to the dose of ethanol, but ACTH rhythm flattened at 0.5 g/kg/day and remained flattened.

Conclusions

The coincidence of elevated ACTH with the initial experience of drinking to intoxication may have altered the mechanisms involved in the transition to heavy drinking.     

The toxicokinetics of mercury in mice offspring after maternal exposure to methylmercury--effect of selenomethionine.

Human evidence indicates fetotoxicity of methylmercury at exposure levels inducing only slight and reversible maternal toxicity, but experimental animal data demonstrate, that fetotoxicity may occur despite absence of noticeable maternal toxicity. However, in contrast to the long-term exposure in humans, the key point in the experimental design of the majority of experimental studies has been administration of few doses of methylmercury late in gestation. The present study in mice therefore used long-term maternal exposure to methylmercury (1 nmol/ml in drinking water) and a cross-fostering design to investigate separately in different offsprings the toxicokinetics of transplacentally absorbed mercury and mercury retained during lactation. Further, the influence of seleno-L-methionine (3 micrograms/ml in drinking water) on the toxicokinetics of methylmercury in these mice was studied. The present study demonstrated, that independent on seleno-L-methionine supplementation, offspring deposited equal amounts of mercury during lactation and during gestation. Moreover, the organ distribution and rate of excretion of mercury in transplacentally exposed mice were considerably different from those in mice exposed postnatally and from adult mice in studies using comparable dosages. Seleno-L-methionine only slightly affected the toxicokinetics of mercury in offspring.     

Interaction of Zidovudine (Azidothymidine) with Isoprinosine and Probenecid in Macaca fascicularis

Pharmaceutical Research -     

Methylmercury: exposure duration and regional distribution as determinants of neurotoxicity in nonhuman primates.

Exposure duration appears to be an important determinant, along with dosage, blood, and brain Hg concentration, of sublethal methylmercury toxicity in macaque and squirrel monkeys. Animals were evaluated for objective neural signs while maintained with blood and brain Hg near equilibrium. Chronic methylmercury, po, produced similar bodily distributions of Hg and neural signs for both species. The characteristic brain regional distribution of Hg is established well in advance of signs, emphasizing the importance of exposure duration and arguing against a major redistribution of Hg as the critical event preceding toxic signs. The calcarine cortex, lateral geniculate, and corpus striatum are candidates for critical brain regions. When near equilibrium, the primate brain Hg concentration is 1.8 to 4.9 times that of whole blood, depending upon region; higher brain/blood ratios are obtained 1 week or more following the end of exposure. Clearance of Hg from most regions of the macaque brain appeared to be similar to the rate of clearance from whole blood ($\text{t}\text{1}\text{2}\text{= 21}\text{days}$) and thus is considerably shorter than half-times reported for primate hair and whole body. The latent period preceding neural signs was inversely related to whole blood Hg concentration within the range associated with neurological signs in humans (0.5–4.5 ppm). Evidence of a “no-effect” dose in the primate will require lower level exposures in excess of 1000 days. This experimental model can suggest critical indices of human longterm, low-level exposures and it provides a basis for evaluating results from nonprimate species.