In vitro delayed response to dihydroartemisinin of malaria parasites infecting sickle cell erythocytes.

BACKGROUND: Decreased efficacy of artemisinin-based combination therapy (ACT) for Plasmodium falciparum malaria has been previously reported in patients with sickle cell disease (SCD). The main purpose of this study was to investigate the in vitro susceptibility of isolates to dihydro-artemisinin (DHA) to provide a hypothesis to explain this treatment failure. METHODS: Isolates were collected from patients attending health centres in Abidjan with uncomplicated P. falciparum malaria. The haemoglobin type has been identified and in vitro drug sensitivity tests were conducted with the ring stage assay and maturation inhibition assay. RESULTS: 134 isolates were obtained. Parasitaemia and haemoglobin levels at inclusion were lower in patients with haemoglobin HbSS and HbSC than in patients with normal HbAA. After ex vivo RSA and drug inhibition assays, the lowest rate of parasitic growth was found with isolates from HbAS red cells. Conversely, a significantly higher survival rate of parasites ranging from 15 to 34% were observed in isolates from HbSS. Isolates with in vitro reduced DHA sensitivity correlate with lower RBC count and haematocrit and higher parasitaemia at inclusion compared to those with isolates with normal DHA sensitivity. However, this decrease of in vitro sensitivity to DHA was not associated with Kelch 13-Propeller gene polymorphism. CONCLUSION: This study highlights an in vitro decreased sensitivity to DHA, for isolates collected from HbSS patients, not related to the Pfkelch13 gene mutations. These results are in line with recent studies pointing out the role of the redox context in the efficacy of the drug. Indeed, SCD red cells harbour a highly different ionic and redox context in comparison with normal red cells. This study offers new insights into the understanding of artemisinin selective pressure on the malaria parasite in the context of haemoglobinopathies in Africa.

Systematic review of e-learning for surgical training.

BACKGROUND: Internet and software-based platforms (e-learning) have gained popularity as teaching tools in medical education. Despite widespread use, there is limited evidence to support their effectiveness for surgical training. This study sought to evaluate the effectiveness of e-learning as a teaching tool compared with no intervention and other methods of surgical training. METHODS: A systematic literature search of bibliographical databases was performed up to August 2015. Studies were included if they were RCTs assessing the effectiveness of an e-learning platform for teaching any surgical skill, compared with no intervention or another method of training. RESULTS: From 4704 studies screened, 87 were included with 7871 participants enrolled, comprising medical students (52 studies), trainees (51 studies), qualified surgeons (2 studies) and nurses (6 studies). E-learning tools were used for teaching cognitive (71 studies), psychomotor (36 studies) and non-technical (8 studies) skills. Tool features included multimedia (84 studies), interactive learning (60 studies), feedback (27 studies), assessment (26 studies), virtual patients (22 studies), virtual reality environment (11 studies), spaced education (7 studies), community discussions (2 studies) and gaming (2 studies). Overall, e-learning showed either greater or similar effectiveness compared with both no intervention (29 and 4 studies respectively) and non-e-learning interventions (29 and 22 studies respectively). CONCLUSION: Despite significant heterogeneity amongst platforms, e-learning is at least as effective as other methods of training.

Coverage and efficacy of intermittent preventive treatment with sulphadoxine pyrimethamine against malaria in pregnancy in Côte d'Ivoire five years after its implementation.

BACKGROUND: The World Health Organization (WHO) recommends for sub-Saharan Africa a package of prompt and effective case-management combined with the delivery of insecticide-treated nets (ITN) and intermittent preventive treatment during pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) through the national antenatal care (ANC) programs. Implemented in Côte d'Ivoire around 2005, few Data on IPTp coverage and efficacy in the country are available. METHODS: A multicentre, cross-sectional survey was conducted in Côte d'Ivoire from September 2009 to May 2010 at six urban and rural antenatal clinics. IPTp-sp coverage, Socio-economic and obstetrical data of mothers and neonate birth weights were documented. Peripheral blood as well as placental and cord blood were used to prepare thick and thin blood films. In addition, pieces of placental tissues were used to prepare impression smears and maternal haemoglobin concentration was measured. Regression logistics were used to study factors associated with placental malaria and LBW (<2.500 grams). RESULTS: A total of 1317 delivered women were enrolled with a median age of 26 years. A proportion of 43.28% of the women had received at least two doses of IPTsp during the current pregnancy although a high proportion (90.4%) of women received antenatal care and made enough visits (≥2). Variability in the results was observed depending on the type of area (rural/urban). Plasmodium falciparum was detected in the peripheral blood of 97 women (7.3%) and in the placenta of 119 women (9%). LBW infants were born to 18.8% (22/107) of women with placental malaria and 8.5% (103/1097) of women without placental malaria. LBW was associated with placental malaria. CONCLUSIONS: This study found relative low coverage of IPTp in the study areas which supported findings that high ANC attendance does not guarantee high IPTp coverage. Urgent efforts are required to improve service delivery of this important intervention.

Effects of topiramate and gabapentin on cognitive abilities in healthy volunteers.

OBJECTIVE: To evaluate the cognitive effects of topiramate (TPM) and gabapentin (GBP). METHODS: Forty healthy volunteers were randomized to a 12-week course of TPM, GBP, or placebo. Doses were gradually escalated over 10 weeks to a maximum of 400 mg/day of TPM or 3,600 mg/day of GBP or to the highest tolerated dose. Subjects were interviewed and examined biweekly. Cognitive testing was performed prior to initiating the drug and again 12 weeks later, at least 2 weeks after achieving plateau dosing. For each subject and cognitive measure, test-retest Z scores were calculated based on regression equations derived from 73 healthy volunteers. Group comparisons utilized the Wilcoxon test. RESULTS: There were significant TPM vs GBP and TPM vs placebo differences in test-retest Z scores for four of six target cognitive measures (Digit Symbol, Story Recall, Selective Reminding, Controlled Oral Word Association), always indicating worse retest performance for subjects receiving TPM. Overall, 12 of 24 cognitive measures were similarly affected. TPM effects were large, and several target measures averaged >2 SD of negative change. One measure was significantly affected by GBP. CONCLUSIONS: Topiramate (TPM) impaired cognitive test performance, whereas gabapentin had minimal effects. The effects of TPM were of sufficient magnitude potentially to affect daily and occupational function.

A multi-laboratory evaluation of a common in vitro pepsin digestion assay protocol used in assessing the safety of novel proteins.

Rationale. Evaluation of the potential allergenicity of proteins derived from genetically modified foods has involved a weight of evidence approach that incorporates an evaluation of protein digestibility in pepsin. Currently, there is no standardized protocol to assess the digestibility of proteins using simulated gastric fluid. Potential variations in assay parameters include: pH, pepsin purity, pepsin to target protein ratio, target protein purity, and method of detection. The objective was to assess the digestibility of a common set of proteins in nine independent laboratories to determine the reproducibility of the assay when performed using a common protocol. Methods. A single lot of each test protein and pepsin was obtained and distributed to each laboratory. The test proteins consisted of Ara h 2 (a peanut conglutin-like protein), beta-lactoglobulin, bovine serum albumin, concanavalin A, horseradish peroxidase, ovalbumin, ovomucoid, phosphinothricin acetyltransferase, ribulose diphosphate carboxylase, and soybean trypsin inhibitor. A ratio of 10U of pepsin activity/microg test protein was selected for all tests (3:1 pepsin to protein, w:w). Digestions were performed at pH 1.2 and 2.0, with sampling at 0.5, 2, 5, 10, 20, 30, and 60min. Protein digestibility was assessed from stained gels following SDS-PAGE of digestion samples and controls. Results. Results were relatively consistent across laboratories for the full-length proteins. The identification of proteolytic fragments was less consistent, being affected by different fixation and staining methods. Overall, assay pH did not influence the time to disappearance of the full-length protein or protein fragments, however, results across laboratories were more consistent at pH 1.2 (91% agreement) than pH 2.0 (77%). Conclusions. These data demonstrate that this common protocol for evaluating the in vitro digestibility of proteins is reproducible and yields consistent results when performed using the same proteins at different laboratories.

Evaluation of travoprost as adjunctive therapy in patients with uncontrolled intraocular pressure while using timolol 0.5%.

PURPOSE: To evaluate the intraocular pressure-lowering efficacy and safety of travoprost 0.0015% and 0.004%, dosed daily in the evening compared with vehicle, in patients with open-angle glaucoma or ocular hypertension, whose intraocular pressure was not adequately controlled on timolol 0.5% twice daily (twice daily). METHODS: Subjects who qualified at screening began a run-in period dosing timolol twice daily for 3 weeks. If the subjects had an intraocular pressure of 24 to 36 mm Hg at 8 AM and 21 to 36 mm Hg at 10 AM and 4 pm in at least one eye on timolol, they were randomized to one of two concentrations of travoprost (0.0015% or 0.004%) or vehicle solution every day and were followed for 6 months. Four hundred twenty-six subjects were randomized. The mean intraocular pressure at 8 AM, 10 AM, and 4 PM in the patient's eye with the higher intraocular pressure was used for the analysis. RESULTS: Mean baseline values (25 mm Hg) for subjects at eligibility (while maintained on timolol) were not significantly different (P <.0001) among the treatment groups. The intraocular pressure was lowered an additional -5.7 to -7.2 mm Hg and -5.1 to -6.7 mm Hg in the travoprost 0.004% and 0.0015% concentrations, respectively. These changes were significantly (P < or =.0001) different from the vehicle group (-1.3 to -2.8 mm Hg). The intraocular pressure range on treatment at all visit times over the 6-month treatment period ranged from 17.9 to 19.2 mm Hg for travoprost 0.004% and 18.3 to 20.1 mm Hg for travoprost 0.0015% compared with 22.4 to 24.1 mm Hg for vehicle. Average hyperemia scores ranged from trace to mild (mean 0.5 on a scale of 0 = none/trace; 1= mild; 2 = moderate; 3 = severe) for all treatment groups. No iris pigmentation changes were observed in any patient during this study. There were no clinically or statistically significant changes from baseline in visual acuity, ocular cells and flare, fundus parameter, cup-to-disk ratio and visual field between the treatment groups. There were no serious adverse events reported for any treatment group. CONCLUSIONS: Travoprost produced clinically relevant and statistically significant additional intraocular pressure reductions from baseline when used adjunctively with timolol in subjects with open-angle glaucoma or ocular hypertension.

Travoprost compared with latanoprost and timolol in patients with open-angle glaucoma or ocular hypertension.

PURPOSE: This study evaluated the safety and intraocular pressure-lowering efficacy of two concentrations of travoprost (0.0015% and 0.004%) compared with latanoprost 0.005% and timolol 0.5% in patients with open-angle glaucoma or ocular hypertension. METHODS: Eight hundred one patients with open-angle glaucoma or ocular hypertension were randomly assigned to travoprost 0.0015%, travoprost 0.004%, latanoprost 0.005%, or timolol 0.5%. The efficacy and safety of travoprost (0.0015% and 0.004%) daily was compared with latanoprost daily and timolol twice daily for a period of 12 months. RESULTS: Travoprost was equal or superior to latanoprost and superior to timolol with mean intraocular pressure over visits and time of day ranging from 17.9 to 19.1 mm Hg (travoprost 0.0015%), 17.7 to 19.1 mm Hg (travoprost 0.004%), 18.5 to 19.2 mm Hg (latanoprost), and 19.4 to 20.3 mm Hg (timolol). For all visits pooled, the mean intraocular pressure at 4 PM for travoprost was 0.7 mm Hg (0.0015%, P =.0502) and 0.8 mm Hg (0.004%, P =.0191) lower than for latanoprost. Travoprost 0.004% was more effective than latanoprost and timolol in reducing intraocular pressure in black patients by up to 2.4 mm Hg (versus latanoprost) and 4.6 mm Hg (versus timolol). Based on a criterion of 30% or greater intraocular pressure reduction from diurnal baseline or intraocular pressure 17 mm Hg or less, travoprost 0.0015% and 0.004% had an overall response to treatment of 49.3% and 54.7%, respectively, compared with 49.6% for latanoprost and 39.0% for timolol. Iris pigmentation change was observed in 10 of 201 of patients (5.0%) receiving travoprost 0.0015%, six of 196 of patients (3.1%) receiving travoprost 0.004%, 10 of 194 of patients (5.2%) receiving latanoprost, and none of the patients receiving timolol (0 of 196). The average ocular hyperemia score was less than 1 on a scale of 0 to 3, indicating that on average patients experienced between none/trace and mild for all treatment groups. There were no serious, unexpected, related adverse events reported for any therapy. CONCLUSIONS: Travoprost (0.0015% and 0.004%), a highly selective, potent prostaglandin F (FP) receptor agonist, is equal or superior to latanoprost and superior to timolol in lowering intraocular pressure in patients with open-angle glaucoma or ocular hypertension. In addition, travoprost 0.004% is significantly better than either latanoprost or timolol in lowering intraocular pressure in black patients. Travoprost is safe and generally well tolerated in the studied patient population.

Respiratory hypersensitivity to diphenylmethane-4,4'-diisocyanate in guinea pigs: comparison with trimellitic anhydride.

Published evidence demonstrates successful induction and elicitation of respiratory hypersensitivity in guinea pigs by the known human respiratory allergens trimellitic anhydride (TMA) and diphenylmethane-4,4'-diisocyanate (MDI). From these data it is apparent that TMA-related respiratory hyperresponsiveness can be elicited readily in guinea pigs upon inhalation challenge with the free chemical. Despite the interlaboratory variability in methodological procedures used for the sensitization as well as elicitation of response and the wide range of concentrations of TMA employed for challenge exposures (6-57 mg/m(3) air), TMA had been unequivocally identified as a benchmark respiratory sensitizer by measurements of the respiratory rate during challenge. The protocols were duplicated to examine the respiratory sensitizer MDI. In intradermally sensitized guinea pigs, changes in immediate-onset-like respiratory response were observed when MDI challenge concentrations exceeded approximately 30 mg MDI/m(3) air. Collective experimental evidence suggests that the respiratory responses observed upon challenge with TMA were markedly more pronounced and easier to identify than those recorded following challenge with MDI or MDI conjugate. In contrast to TMA, irritant concentrations of MDI had to be used to elicit any respiratory response and the differentiation of irritant and allergic responsiveness became increasingly difficult. Despite the absence of unequivocal changes in breathing patterns upon MDI challenge, MDI-sensitized animals displayed elevated anti-MDI immunoglobulin G1 (IgG1) antibodies, and a significant influx of eosinophilic granulocytes in the bronchial wall and lung-associated lymph nodes. Therefore, it is believed that the robustness of this animal model to identify low-molecular-weight agents as respiratory sensitizer is increased when several endpoints are considered. These are (1) positive respiratory response upon challenge with the hapten, and if negative, also challenge with the conjugate of the hapten; (2) an influx of eosinophilic granulocytes; and (3) increased specific IgG1 response. Furthermore, it appears that particles in the range of approximately 2-6 microm evoke more consistent respiratory response upon challenge exposure than particles in the 1-2 microm range.

In vivo skin decontamination of methylene bisphenyl isocyanate (MDI): soap and water ineffective compared to polypropylene glycol, polyglycol-based cleanser, and corn oil.

In the home and workplace, decontamination of a chemical from skin is traditionally done with a soap-and-water wash, although some workplaces may have emergency showers. It has been assumed that these procedures are effective, yet workplace illness and even death occur from chemical contamination. Water, or soap and water, may not be the most effective means of skin decontamination, particularly for fat-soluble materials. This study was undertaken to help determine whether there are more effective means of removing methylene bisphenyl isocyanate (MDI), a potent contact sensitizer, from the skin. MDI is an industrial chemical for which skin decontamination, using traditional soap and water and nontraditional polypropylene glycol, a polyglycol-based cleanser (PG-C), and corn oil were all tried in vivo on the rhesus monkey, over 8 h. Water, alone and with soap (5% and 50% soap), were partially effective in the first h after exposure, removing 51-69% of the applied dose. However, decontamination fell to 40-52% at 4 h and 29-46% by 8 h. Thus, the majority of MDI was not removed by the traditional soap-and-water wash; skin tape stripping after washing confirmed that MDI was still on the skin. In contrast, polypropylene glycol, PG-C, and corn oil all removed 68-86% of the MDI in the first h, 74-79% at 4 h, and 72-86% at 8 h. Statistically, polypropylene glycol, PG-C, and corn oil were all better (p < 0.05) than soap and water at 4 and 8 h after dose application. These results indicate that a traditional soap-and-water wash and the emergency water shower are relatively ineffective at removing MDI from the skin. More effective decontamination procedures, as shown here, are available. These procedures are consistent with the partial miscibility of MDI in corn oil and polyglycols.

Developmental toxicity evaluation of inhaled toluene diisocyanate vapor in CD rats.

Mated female CD (Sprague-Dawley) rats, 25/group, were exposed to toluene diisocyanate (TDI) vapor, for six h/day on gestational days (gd) 6 through 15, at 0.00, 0.02, 0.10, or 0.50 p.p.m.. Maternal clinical signs, body weights, and feed and water consumption were recorded throughout gestation. At termination (gd 21), maternal body, gravid uterine, and liver weights were recorded. Corpora lutea were counted, and implantation sites were identified: resorptions and dead and live fetuses. All live fetuses were examined for external alterations. One-half of the live fetuses/litter were examined for visceral (including craniofacial) alterations. The remaining intact fetuses/litter were stained with alizarin red S and examined for ossified skeletal alterations. Maternal toxicity at 0.50 ppm consisted of reduced body weights, body weight gains, feed consumption, and clinical signs of toxicity. Water consumption was unaffected. Gestational parameters exhibited no significant treatment-related changes, including pre- and postimplantation loss, sex ratio/litter, or fetal body weights/litter. Incidences of individual malformations, malformations by category (external, visceral, and skeletal), total malformations, individual external and visceral variations, variations by category, and total variations were unaffected. Of 111 skeletal variants observed, only 1, incidence of poorly ossified cervical centrum 5, was increased at 0.50 ppm, indicating possible minimal fetotoxicity, although it occurred in the absence of any other indications of developmental toxicity. Therefore, exposure to TDI vapor by inhalation, during major organogenesis in CD rats, resulted in maternal toxicity and minimal fetotoxicity at 0.50 ppm no observed adverse effect level (NOAEL) for maternal and developmental toxicity was 0.10 ppm. No treatment-related embryotoxicity or teratogenicity was observed.

Two-generation reproductive toxicity study of inhaled toluene diisocyanate vapor in CD rats.

Twenty-eight 42-day-old pups/sex/group (F0) were exposed to toluene diisocyanate vapor (TDI; 80% 2,4-TDI, 20% 2,6-TDI) by inhalation at 0.0, 0.02, 0.08, or 0.3 ppm, 6 h/day, 5 days/week, for 10 weeks, then mated within groups for 3 weeks, with exposure 7 days/week during mating, gestation, and lactation. F0 maternal animals were not exposed from gestational day (gd) 20 through postnatal day (pnd) 4; maternal exposures resumed on pnd 5. Twenty-eight weanlings/sex/group continued exposure for 12 weeks (starting on pnd 28) and were bred as described above. F0 and F1 parents and ten F1 and F2 weanlings/sex/group were necropsied, and adult reproductive organs, pituitary, liver, kidneys, and upper respiratory tract (target organs) were evaluated histologically in ten/sex/group. Adult toxicity was observed in both sexes and generations at 0.08 and 0.3 ppm, including occasional reductions in body weights and weight gain, clinical signs of toxicity at 0.08 and 0.3 ppm, and histologic changes in the nasal cavities at 0.02, 0.08, and 0.3 ppm (including rhinitis, a nonspecific response to an irritating vapor, at all concentrations). There was no reproductive toxicity, reproductive organ pathology, or effect on gestation or lactation at any exposure concentration. Postnatal toxicity and reduced body weights and weight gains during lactation occurred only in F2 litters at 0.08 and 0.3 ppm. Therefore, under the conditions of this study, a no observed adverse effect level (NOAEL) was not determined for adult toxicity; the NOAEL for reproductive toxicity was at least 0.3 ppm, and the NOAEL for postnatal toxicity was 0.02 ppm.

Consanguinity and kinship in Down syndrome in Saguenay Lac-Saint-Jean (Québec).

Genealogies of 67 cases of Down syndrome (DS) cytogenetically proven as trisomy 21 born in Saguenay-Lac-Saint-Jean were reconstructed using a population register. Genealogies of three controls for each patient matched on sex, date and place of birth were also reconstructed. The mean kinship coefficient was slightly, but not significantly (p > 0.05), increased in the DS group compared to the control group (0.000222 versus 0.000165). The increase was mostly the result of two patients being related as uncle-nephew. The mean inbreeding coefficient was also higher, although not significantly (p > 0.05), in the DS group than in the control group (0.001348 versus 0.000848). Nine consanguineous marriages (13.4%) were identified in the DS group compared to 17 of 201 (8.5%) in the control group. These results may suggest, as previously reported by Roberts et al. in Shetland, that some recessive element is involved in the etiology of DS, possibly in preventing the loss of the trisomic 21 fetus.

Chronic toxicity and oncogenicity of picloram in Fischer 344 rats.

The chronic toxicity and oncogenicity of the herbicide picloram was studied in male and female Fischer 344 rats administered 0, 20, 60, or 200 mg/kg.d technical-grade picloram via their feed for 2 yr. A comprehensive set of in-life and clinical pathology parameters was measured and an extensive list of tissues was examined grossly and by light microscopy from control and treatment groups of animals. The primary treatment-related effect observed in the study was hepatocellular swelling and altered tinctorial properties in the central regions of the liver lobules of both sexes of rats ingesting 60 or 200 mg/kg.d picloram. Males were more affected than females. Increases in liver weights accompanied these changes in both sexes of rats ingesting the high dose level of picloram. All other histopathologic lesions observed were typical of those that normally occur in aged Fischer 344 rats. There were no treatment-related increases in the incidence of any particular tumor type or in total tumors. No treatment-related effects were observed in rats ingesting 20 mg/kg.d of the test material.

Chlorpyrifos: a 13-week nose-only vapor inhalation study in Fischer 344 rats.

Fischer 344 rats were exposed by the nose-only inhalation route to chlorpyrifos vapors at concentrations of 0, 5.2, 10.3, or 20.6 ppb, 6 hr/day, 5 days/week for 13 weeks. The exposure concentrations were limited by the low vapor pressure of chlorpyrifos (theoretical maximum vapor concentration of 25 ppb at 25 degrees C). No treatment-related signs of toxicity or changes in body weights were detected during the course of the study. Urinalysis, hematology, clinical chemistry, organ weights, gross pathologic, and histopathologic evaluations were performed at the end of the study with no treatment-related effects observed. In addition, no differences from controls were noted in plasma, red blood cell, or brain cholinesterase activities. The results of this study indicate that the no-observed-effect level for chlorpyrifos vapor was the highest attainable concentration, 20.6 ppb, in male and female Fischer 344 rats.

Ethyl chloride: 11-day continuous exposure inhalation toxicity study in B6C3F1 mice.

Groups of seven B6C3F1 mice per sex were exposed for 23 hr/day to 0, 250, 1250, or 5000 ppm ethyl chloride (EtCl) for 11 consecutive days to evaluate the potential toxicity of EtCl under near-continuous exposure conditions. On the day following the last exposure, a neurobehavioral observation battery was performed, samples were obtained for clinical chemistry and hematology, and necropsies were conducted. Histopathologic examination was subsequently performed. The only observed effects were increased relative liver weights and a slight increase in hepatocellular vacuolation (glycogen or fat) in 5000 ppm-exposed mice. Exposures to EtCl were well tolerated despite the unusually long exposure periods.

Dietary toxicity of picloram herbicide in rats.

The toxicity of orally administered technical-grade picloram was evaluated in male and female Fischer 344 rats. Dietary dose levels were up to 2000 mg/kg body weight (bw) X d for 2 wk, 500 mg/kg bw X d for 13 wk, or 200 mg/kg bw X d for 12 mo. Routine indices of toxicity were evaluated at all of the respective time periods. Body weight, food consumption, clinical chemistries, urinalyses, and hematological determinations were considered unaffected by treatment. The only treatment-related effect, regardless of the duration of exposure, was in the liver of both male and female rats. This was generally manifested as an increase in the liver-to-body weight ratio and slight hypertrophy and pallor of the centrilobular hepatocytes. These effects were consistently present in rats receiving 1000 mg/kg bw X d for 2 wk, 300 mg/kg bw X d for 13 wk, or 200 mg/kg bw X d for 6 or 12 mo. Similar effects were marginally evident for rats receiving 500 mg/kg bw X d for 2 wk, 150 mg/kg bw X d for 13 wk, or 60 mg/kg bw X d for 6 or 12 mo. At 60 mg/kg bw X d, the effects were not progressive from 6 to 12 mo. The no-observable-effect level (NOEL) was 20 mg/kg bw X d for male and female rats fed picloram for 12 mo.

Pharmacokinetics of inhaled methyl chloride (CH3Cl) in male volunteers.

Six volunteers, 25-41 years of age, were exposed for 6 hr on separate days to 50 and 10 ppm of CH3Cl. Blood and expired air CH3Cl concentrations reached an apparent plateau during the first hour of the exposure and were proportional to the exposure concentration. Consistent with previous reports, the volunteers could be separated into two discrete groups based on the differences observed in their blood and expired air CH3Cl concentrations. Both groups eliminated CH3Cl rapidly once the exposure was terminated, but CH3Cl was eliminated more rapidly by those volunteers with the lower blood and expired air CH3Cl concentrations. The existence of these two groups can be explained by a twofold difference in the rate at which they metabolized CH3Cl; however, this difference is of questionable toxicological significance. Urinary excretion of the putative metabolite S-methyl cysteine was not related to the exposure; thus, it is not a valid means of monitoring occupational exposure to CH3Cl.

Neurotoxicity of methyl chloride in continuously versus intermittently exposed female C57BL/6 mice.

This study evaluated the relationship between methyl chloride (MeCl) exposure duration and neurotoxicity. Female C57BL/6 mice were exposed to MeCl for 11 days, either continuously (22 hr/day) to 15, 50, 100, 150, or 200 ppm, or intermittently (5.5 hr/day) to 150, 400, 800, 1600, or 2400 ppm. This strain and sex of mouse was chosen because it is sensitive to MeCl neurotoxicity and was a good candidate to allow the evaluation of morphological effects and the quantitation of functional effects. A simple quantitative relationship between neurotoxicity and continuous vs intermittent exposure was not observed. Although the no-observable-effect levels for continuous and intermittent MeCl exposures were very nearly proportionate to exposure concentration multiplied by duration, the dose-response curve was much steeper for continuously exposed mice. Cerebellar granular cell layer degeneration was observed in mice exposed continuously to 100 ppm MeCl and in mice exposed intermittently to 400 ppm. This histopathologic effect was observed at lower concentrations than a decrement in rotating rod running performance. No effects were observed in mice exposed to 50 ppm continuously or to 150 ppm intermittently. Continuous exposure to MeCl produced the cerebellar lesion with less effect on other tissues than did intermittent exposure. In mice exposed to 2400 ppm intermittently, there were renal and hematopoietic effects in addition to relatively slight cerebellar granular cell layer degeneration. These 2400-ppm exposed mice developed hemoglobinuria, apparently as a result of intravascular hemolysis. Although the effect of exposure duration on MeCl toxicity was complex, this study indicated that careful judgment is necessary when extrapolating intermittent exposure data to a continuous exposure situation.

Ethylene glycol monomethyl ether and propylene glycol monomethyl ether: metabolism, disposition, and subchronic inhalation toxicity studies.

Short-term and subchronic vapor inhalation studies have shown that there are pronounced differences in the toxicological properties of ethylene glycol monomethyl ether (EGME) and propylene glycol monomethyl ether (PGME). Overexposure to EGME has resulted in adverse effects on testes, bone marrow and lymphoid tissues in laboratory animals. PGME does not affect these tissues, and instead, overexposure to PGME has been associated with increases in liver weight and central nervous system depression. EGME is primarily oxidized to methoxyacetic acid in male rats, while PGME apparently undergoes O-demethylation to form propylene glycol. Since methoxyacetic acid has been shown to have the same spectrum of toxicity as EGME in male rats, the observed differences in the toxicological properties of EGME and PGME are thought to be due to the fact that the two materials are biotransformed via different routes to different types of metabolites.