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Results for “benchmark dose analysis”

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PubMed1994

Summary of the workshop on issues in risk assessment: quantitative methods for developmental toxicology.

This report summarizes the proceedings of a conference on quantitative methods for assessing the risks of developmental toxicants. The conference was planned by a subcommittee of the National Research Council's Committee on Risk Assessment Methodology in conjunction with staff from several federal agencies, including the U.S. Environmental Protection Agency, U.S. Food and Drug Administration, U.S. Consumer Products Safety Commission, and Health and Welfare Canada. Issues discussed at the workshop included computerized techniques for hazard identification, use of human and animal data for defining risks in a clinical setting, relationships between end points in developmental toxicity testing, reference dose calculations for developmental toxicology, analysis of quantitative dose-response data, mechanisms of developmental toxicity, physiologically based pharmacokinetic models, and structure-activity relationships. Although a formal consensus was not sought, many participants favored the evolution of quantitative techniques for developmental toxicology risk assessment, including the replacement of lowest observed adverse effect levels (LOAELs) and no observed adverse effect levels (NOAELs) with the benchmark dose methodology.

Animals↗

PubMed2002

A technique for microsecond heating and cooling of a thin (submicron) biological sample.

Temperature excursions of short duration are useful in exploring the effects of stress on biological systems. Stress will affect the conformation of biological molecules such as proteins, which will lead to an effect on their function. The feasibility of generating such temperature excursions is demonstrated by solving the heat diffusion equation for an aqueous layer on a silicon wafer. The silicon is rapidly heated by a laser pulse and also acts as a heat sink to quench the temperature rise. An oxide layer was used to limit the maximum temperature attained by the sample. We show that exposures above a 50 degrees C benchmark can be confined to times less than 5 micros.

Cold Temperature↗

PubMed1995

Implications of tissue heterogeneity for radiosurgery in head and neck tumors.

PURPOSE: This study was undertaken to investigate the perturbation of small radiation beams by low density heterogeneities and to evaluate the ability of a Monte Carlo code to account for such perturbation. Performance of an inexpensive film scanning system was also evaluated. METHODS AND MATERIALS: Film and diode measurements were made in an acrylic phantom in which the size and position of an air gap were varied. Monte Carlo analysis was used to obtain additional verification of the measurements, to provide insight into photon and electron transport phenomena not directly measurable, and as a benchmark for the code. RESULTS: With 10 MV photons and a 1 cm circular field, a small 3-mm air cavity placed 2.6 cm deep in acrylic (full buildup) results in a reduction in central axis dose of 21% immediately following the cavity. Equilibrium is then reestablished over the next centimeter, after which the dose exceeds that of the homogeneous case by 3-4%. The loss in central axis equilibrium is highly field-size dependent, with some loss occurring even for the largest (32 mm) collimator. In addition, the presence of the air cavity produces a significant increase in dose up to 2 cm lateral and outside the primary field. CONCLUSIONS: Tissue heterogeneities are not presently accounted for in radiosurgery calculations, yet have the ability to perturb dose significantly. Targets may potentially be underdosed, and adjacent critical structures overdosed. Inability to account for tissue heterogeneities may limit the use of the radiosurgery approach in some areas. A Monte Carlo approach may be the method of choice for small field dose calculation when tissue heterogeneities are encountered.

Air↗

PubMed2004

Angiotensin-converting enzyme inhibitor use in elderly patients hospitalized with heart failure and left ventricular systolic dysfunction.

PURPOSE: Although angiotensin-converting enzyme (ACE) inhibitors are recommended for all patients with systolic heart failure, prior studies suggest that elderly cohorts are less likely to receive such therapy. The purpose of this study was to determine the age dependence of adherence to guideline-based medical care in hospitalized heart failure patients. METHODS: We performed a multicenter observational cohort study including 613 patients admitted to participating hospitals with a primary diagnosis of heart failure with ejection fraction < or =40%. This cohort was divided into four age groups (group 1: <60, group 2: 60-69, group 3: 70-79, and group 4: 80 years) and adherence to guideline-based medical care was measured. RESULTS: ACE inhibitors were administered to 83% of ideal heart failure patients, and this rate was similar for all age groups. Elderly patients received significantly lower ACE inhibitor dosages compared to their younger counterparts (168, 148, 125 and 117 mg captopril in groups 1, 2, 3, and 4, respectively, p=0.001). Lower creatinine clearance (p<0.001), prior residence in a long-term care facility (p=0.037), intolerance to ACE inhibitors (p=0.006), lower blood pressure (p=0.005), absence of a history of hypertension (p=0.005), and no prior heart failure hospitalizations within the past year (p=0.001) were found to be independent predictors of low ACE inhibitor dosing. CONCLUSIONS: In this heart failure benchmarking project, elderly patients received guideline-based ACE inhibitor therapy at similar rates, but at lower doses, compared to their younger counterparts.

Age Distribution↗

PubMed2006

Within-animal variation as an indication of the minimal magnitude of the critical effect size for continuous toxicological parameters applicable in the benchmark dose approach.

In this study, the within-animal variation in routinely studied continuous toxicological parameters was estimated from temporal fluctuations in individual healthy nonexposed animals. Assuming that these fluctuations are nonadverse, this within-animal variation may be indicative of the minimal magnitude of the critical effect size (CES). The CES is defined as the breaking point between adverse and nonadverse changes in a continuous toxicological parameter, at the level of the individual organism. The total variation in the data from individual nonexposed animals was divided in variation parts due to known factors (differences in sex, animal, and day) and a residual variation, by means of analysis of variance. Using the residual variation and the estimated analytical measurement error of a toxicological parameter, the within-animal variation can be estimated. The data showed within-animal variations ranging between 0.6% and 34% for different clinical chemistry and hematological parameters in 90-day rat studies. This indicates that different (minimal) CES values may be applicable for different parameters.

Analysis of Variance↗

PubMed2005

Analyses of neurobehavioral screening data: dose-time-response modeling of continuous outcomes.

Neurotoxic effects are a non-cancer endpoint for health risk, and neurobehavioral screening tests can serve as a first tier investigation of neurotoxicity [US EPA, Federal Register 63 (1998) 26926]. Analysis of neurobehavioral screening data such as those of the functional observational battery (FOB) traditionally relies on analysis of variance (ANOVA). ANOVA is designed to detect whether there are dose-effects, but does not model the underlying dose-response relationship and subsequent risk assessment fails to utilize the shape of the underlying dose-response. In contrast, dose-response modeling interpolates toxic effects between experimental points, and permits prediction of toxic effects within the experimental range. Additionally it is also a prerequisite for estimating a benchmark dose. This paper discusses dose-time-response modeling of longitudinal neurotoxicity data and illustrates the methods using three continuous FOB outcomes from an EPA study involving acute exposure to triethyltin (TET). Several mathematical functions are presented as candidate dose-time-response models. The use of random effects is discussed to characterize inter-subject variation. The results indicate that it is feasible to use simple mathematical functions to model empirical dose-time-response observed in existing longitudinal neurotoxicological data. Further research is needed on the types of design and data required to reliably approximate the true underlying dose-time-response.

Behavior↗

PubMed2005

Development of a chronic inhalation reference level for respirable crystalline silica.

Chronic inhalation exposure of workers to crystalline silica can result in silicosis. The general public can also be exposed to lower levels of crystalline silica from quarries, sand blasting, and entrained fines particles from surface soil. We have derived an inhalation chronic reference exposure level for silica, a level below which no adverse effects due to prolonged exposure would be expected in the general public. Incidence of silicosis and silica exposure data from a cohort of 2235 white South African gold miners yielded a reference level of 3 microg/m3) for respirable silica (particle size as defined occupationally) using a benchmark concentration approach. Data from cohorts of American gold miners, Chinese tin miners, diatomaceous earth workers, and black South African gold miners yielded similar results with a range of 3-10 microg/m3. Strengths of the chronic reference exposure level include the availability of several large long-term studies of inhalation in workers at varying exposure concentrations, adequate histopathological and radiologic analysis, adequate follow-up of exposed workers, a dose-response effect in several studies, observation of a No Observed Adverse Effect Level in the key study, and the power of the key study to detect a small effect. Uncertainties include the general underestimation of silicosis by radiography alone and the uncertainties in exposure estimation.

China↗

PubMed2000

Inhaled beclomethasone versus placebo for chronic asthma.

BACKGROUND: Inhaled beclomethasone diproprionate (BDP) has been, together with inhaled budesonide, the mainstay of anti-inflammatory therapy for asthma for many years. A range of new prophylactic therapies for asthma is becoming available and BDP is now frequently used as the reference treatment against which these newer agents are being compared. OBJECTIVES: The objectives of this review were to: a) Compare the efficacy of BDP with placebo in the treatment of chronic asthma. b) Explore the possibility that a dose response relationship exists for BDP in the treatment of chronic asthma. c) To provide the best estimate of the efficacy of BDP as a benchmark for evaluation of newer asthma therapies. SEARCH STRATEGY: We searched the Cochrane Airways Group Trial Register (1999) and reference lists of articles. We contacted trialists and Glaxo Wellcome for additional studies and searched abstracts of major respiratory society meetings (1997-1999). SELECTION CRITERIA: Randomised trials in children and adults comparing BDP to placebo in the treatment of chronic asthma. Two reviewers independently assessed articles for inclusion and methodological quality. DATA COLLECTION AND ANALYSIS: One reviewer extracted data; authors were contacted to clarify missing information. Quantitative analyses where undertaken using Review Manager (Revman) 4.0.3 with Metaview 3.1. MAIN RESULTS: 52 studies were selected for inclusion (3459 subjects). The studies were generally of high methodological quality. In non-oral steroid treated patients, BDP produced significant improvements in a number of efficacy measures compared to placebo including FEV1 weighted mean difference (WMD) 340ml (95% CI 190-500ml); FEV1 (% predicted) WMD 6% (95% CI 0.4 to 11.5%) and morning PEFR WMD 50 L/min (95% CI 8 to 92 L/min). BDP also led to reductions in rescue beta2 agonist use compared to placebo WMD 1.75 puffs/d (95% CI 1.4 to 2.4 puffs/d) and reduced the likelihood of trial withdrawal due to asthma exacerbation relative risk (RR) 0.26 (95% CI 0.15 to 0.43). In oral steroid treated patients BDP led to significantly greater reductions in oral prednisolone use WMD 5 mg/d (95% CI 4 to 6 mg/d) and a higher likelihood of discontinuing oral prednisolone RR 0.54 (95% CI 0.43 to 0.67). There was little evidence for a clincially worthwhile dose response effect, but few studies recruited patients with more severe asthma. REVIEWER'S CONCLUSIONS: This review has quantified the efficacy of BDP in the treatment of chronic asthma and strongly supports its use. Current asthma guidelines recommend titration of dose to individual patient response, but the published data provide little support for dose titration above 400 mcg/d in patients with mild to moderate asthma. There are insufficient data to draw any conclusions concerning dose-response in patients with severe disease.

Administration, Inhalation↗

PubMed2006

Estimation of the benchmark dose by structural equation models.

While epidemiological data typically contain a multivariate response and often also multiple exposure parameters, current methods for safe dose calculations, including the widely used benchmark approach, rely on standard regression techniques. In practice, dose-response modeling and calculation of the exposure limit are often based on the seemingly most sensitive outcome. However, this procedure ignores other available data, is inefficient, and fails to account for multiple testing. Instead, risk assessment could be based on structural equation models, which can accommodate both a multivariate exposure and a multivariate response function. Furthermore, such models will allow for measurement error in the observed variables, which is a requirement for unbiased estimation of the benchmark dose. This methodology is illustrated with the data on neurobehavioral effects in children prenatally exposed to methylmercury, where results based on standard regression models cause an underestimation of the true risk.

Biometry↗

PubMed2005

Voxel model in BNCT treatment planning: performance analysis and improvements.

In recent years, many efforts have been made to study the performance of treatment planning systems in deriving an accurate dosimetry of the complex radiation fields involved in boron neutron capture therapy (BNCT). The computational model of the patient's anatomy is one of the main factors involved in this subject. This work presents a detailed analysis of the performance of the 1 cm based voxel reconstruction approach. First, a new and improved material assignment algorithm implemented in NCTPlan treatment planning system for BNCT is described. Based on previous works, the performances of the 1 cm based voxel methods used in the MacNCTPlan and NCTPlan treatment planning systems are compared by standard simulation tests. In addition, the NCTPlan voxel model is benchmarked against in-phantom physical dosimetry of the RA-6 reactor of Argentina. This investigation shows the 1 cm resolution to be accurate enough for all reported tests, even in the extreme cases such as a parallelepiped phantom irradiated through one of its sharp edges. This accuracy can be degraded at very shallow depths in which, to improve the estimates, the anatomy images need to be positioned in a suitable way. Rules for this positioning are presented. The skin is considered one of the organs at risk in all BNCT treatments and, in the particular case of cutaneous melanoma of extremities, limits the delivered dose to the patient. Therefore, the performance of the voxel technique is deeply analysed in these shallow regions. A theoretical analysis is carried out to assess the distortion caused by homogenization and material percentage rounding processes. Then, a new strategy for the treatment of surface voxels is proposed and tested using two different irradiation problems. For a parallelepiped phantom perpendicularly irradiated with a 5 keV neutron source, the large thermal neutron fluence deviation present at shallow depths (from 54% at 0 mm depth to 5% at 4 mm depth) is reduced to 2% on average. Reassigning fluence values in the case of this phantom in angular position produced the maximum deviation in the thermal fluence to decrease from 140% to 23% at the surface of the phantom. Thus, even for the largest deviations, obtained by intentionally placing the phantom in the most disadvantageous position with respect to the voxel grid, the reassignment shows very good performance. Since these results substantially improve the performance of the 1 cm based voxel model in surface boundary regions, the proposed strategy will be implemented in future versions of the NCTPlan code.

Boron Neutron Capture Therapy↗

PubMed2005

Quantitative risk assessment for multivariate continuous outcomes with application to neurotoxicology: the bivariate case.

The neurotoxic effects of chemical agents are often investigated in controlled studies on rodents, with multiple binary and continuous endpoints routinely collected. One goal is to conduct quantitative risk assessment to determine safe dose levels. Such studies face two major challenges for continuous outcomes. First, characterizing risk and defining a benchmark dose are difficult. Usually associated with an adverse binary event, risk is clearly definable in quantal settings as presence or absence of an event; finding a similar probability scale for continuous outcomes is less clear. Often, an adverse event is defined for continuous outcomes as any value below a specified cutoff level in a distribution assumed normal or log normal. Second, while continuous outcomes are traditionally analyzed separately for such studies, recent literature advocates also using multiple outcomes to assess risk. We propose a method for modeling and quantitative risk assessment for bivariate continuous outcomes that address both difficulties by extending existing percentile regression methods. The model is likelihood based; it allows separate dose-response models for each outcome while accounting for the bivariate correlation and overall characterization of risk. The approach to estimation of a benchmark dose is analogous to that for quantal data without the need to specify arbitrary cutoff values. We illustrate our methods with data from a neurotoxicity study of triethyl tin exposure in rats.

Animals↗

PubMed2003

Methods and rationale for derivation of a reference dose for methylmercury by the U.S. EPA.

In 2001, the U.S. Environmental Protection Agency derived a reference dose (RfD) for methylmercury, which is a daily intake that is likely to be without appreciable risk of deleterious effects during a lifetime. This derivation used a series of benchmark dose (BMD) analyses provided by a National Research Council (NRC) panel convened to assess the health effects of methylmercury. Analyses were performed for a number of endpoints from three large longitudinal cohort studies of the neuropsychological consequences of in utero exposure to methylmercury: the Faroe Islands, Seychelles Islands, and New Zealand studies. Adverse effects were identified in the Faroe Islands and New Zealand studies, but not in the Seychelles Islands. The NRC also performed an integrative analysis of all three studies. The EPA applied a total uncertainty factor (UF) of 10 for intrahuman toxicokinetic and toxicodynamic variability and uncertainty. Dose conversion from cord blood mercury concentrations to maternal methylmercury intake was performed using a one-compartment model. Derivation of potential RfDs from a number of endpoints from the Faroe Islands study converged on 0.1 microg/kg/day, as did the integrative analysis of all three studies. EPA identified several areas for which further information or analyses is needed. Perhaps the most immediately relevant is the ratio of cord:maternal blood mercury concentration, as well as the variability around this ratio. EPA assumed in its dose conversion that the ratio was 1.0; however, available data suggest it is perhaps 1.5-2.0. Verification of a deviation from unity presumably would be translated directly into comparable reduction in the RfD. Other areas that EPA identified as significant areas requiring further attention are cardiovascular consequences of methylmercury exposure and delayed neurotoxicity during aging as a result of previous developmental or adult exposure.

Cohort Studies↗

PubMed2001

Exposure-disease continuum for 2-chloro-2'-deoxyadenosine, a prototype ocular teratogen. 1. Dose-response analysis.

BACKGROUND: Treatment of pregnant mice with 2-chloro-2'-deoxyadenosine (2CdA) on day 8 of gestation induces microphthalmia through a mechanism coupled to the p53 tumor suppressor gene. The present study defines 2CdA dosimetry with respect to exposure (pharmacokinetics), p53 protein induction, and disease (microphthalmia). METHODS: Pregnant CD-1 mice dosed with 0.5-10.0 mg/kg 2CdA on day 8 provided fetuses for teratological evaluation; 2CdA was measured by HPLC in the antimesometrium through 180 min postexposure, and p53 was assessed with immunostaining of the embryo through 270 min. 5'-/3'-RACE was used to sequence the candidate gene for 2CdA bioactivation from target cells. RESULTS: Microphthalmia appeared first in the dose-response curve. The highest 2CdA dose having no observable adverse effect (NOAEL) was 1.5 mg/kg; the benchmark dose that produced an extra 5% risk of microphthalmia (BMD(5)) was 2.5 mg/kg, and the lower confidence limit (BMDL) was 2.0 mg/kg. Pharmacokinetic parameters for doses encompassing the threshold (1.5-2.5 mg/kg) were modeled at 1.0-1.8 microM (C(max)) and 30-80 microM-min (AUC). The p53 response was not detected below the BMDL; however, a low-grade response appeared 4.5 hr after a teratogenic dose (5.0 mg/kg), and high-grade induction followed an embryolethal dose (10.0 mg/kg). RACE identified a novel splice variant of mitochondrial deoxyguanosine kinase, dGK-3, as the likely candidate for 2CdA bioactivation in the embryo. CONCLUSIONS: Microphthalmia represented the critical effect malformation of 2CdA. The findings suggest a mitochondrial mechanism for 2CdA bioactivation, leading to an embryonic p53 response only after 2CdA elimination and implying pharmacodynamic coupling to the exposure-disease continuum. Published 2001 Wiley-Liss, Inc.

Amino Acid Sequence↗

PubMed2002

Development of an agricultural job-exposure matrix for British Columbia, Canada.

Farmers in British Columbia (BC), Canada have been shown to have unexplained elevated proportional mortality rates for several cancers. Because agricultural exposures have never been documented systematically in BC, a quantitative agricultural Job-exposure matrix (JEM) was developed containing exposure assessments from 1950 to 1998. This JEM was developed to document historical exposures and to facilitate future epidemiological studies. Available information regarding BC farming practices was compiled and checklists of potential exposures were produced for each crop. Exposures identified included chemical, biological, and physical agents. Interviews with farmers and agricultural experts were conducted using the checklists as a starting point. This allowed the creation of an initial or 'potential' JEM based on three axes: exposure agent, 'type of work' and time. The 'type of work' axis was determined by combining several variables: region, crop, job title and task. This allowed for a complete description of exposures. Exposure assessments were made quantitatively, where data allowed, or by a dichotomous variable (exposed/unexposed). Quantitative calculations were divided into re-entry and application scenarios. 'Re-entry' exposures were quantified using a standard exposure model with some modification while application exposure estimates were derived using data from the North American Pesticide Handlers Exposure Database (PHED). As expected, exposures differed between crops and job titles both quantitatively and qualitatively. Of the 290 agents included in the exposure axis; 180 were pesticides. Over 3000 estimates of exposure were conducted; 50% of these were quantitative. Each quantitative estimate was at the daily absorbed dose level. Exposure estimates were then rated as high, medium, or low based on comparing them with their respective oral chemical reference dose (RfD) or Acceptable Daily Intake (ADI). This data was mainly obtained from the US Environmental Protection Agency (EPA) Integrated Risk Information System database. Of the quantitative estimates, 74% were rated as low (< 100%) and only 10% were rated as high (>500%). The JEM resulting from this study fills a void concerning exposures for BC farmers and farm workers. While only limited validation of assessments were possible, this JEM can serve as a benchmark for future studies. Preliminary analysis at the BC Cancer Agency (BCCA) using the JEM with prostate cancer records from a large cancer and occupation study/survey has already shown promising results. Development of this JEM provides a useful model for developing historical quantitative exposure estimates where is very little documented information available.

Agricultural Workers' Diseases↗

PubMed2000

Management of anaemia in United Kingdom renal units: a report from the UK Renal Registry.

BACKGROUND: Morbidity and mortality of patients undergoing renal replacement therapy is influenced by the adequacy of correction of renal anaemia. The Renal Association has set standards for attainment of a target haemoglobin of 10 g/dl. This study compared the management of anaemia in dialysis patients in nine renal units in the UK. METHODS: A cross-sectional analysis was carried out on data submitted electronically to the UK Renal Registry. There were 1449 haemodialysis patients and 741 peritoneal dialysis patients in the nine renal centres analysed. Individual patient data were collected on haemoglobin, ferritin, erythropoietin prescription, and pre- and post-dialysis urea concentrations. RESULTS: None of the centres achieved the standard of more than 80% of haemodialysis patients with a haemoglobin of greater than 10 g/dl. Three centres achieved this standard for peritoneal dialysis. There was wide variation between centres in the percentage reaching the target. Differences in ferritin, erythropoietin prescription, and dialysis doses between centres could not entirely explain the variations between centres. Females had lower haemoglobin than males despite a greater proportion being treated with erythropoietin. There was a trend of increasing haemoglobin concentration during the study period in haemodialysis but not in peritoneal dialysis patients. CONCLUSIONS: The Renal Association standards for management of anaemia are not being met. The data allow renal centres to compare their practices with others to identify areas that might be improved. Further analysis may allow a benchmark to be determined of what it is possible to achieve by best practice.

Aging↗

PubMed2026

scGPA: an LLM-assisted workflow for directional virtual gene perturbation analysis from single-cell transcriptomes.

BACKGROUND: Existing virtual perturbation methods can often infer directional changes by comparing predicted post-perturbation expression profiles with control cells. However, workflows that directly return direction-specific downstream candidate genes together with confidence scores, evidence support and interpretable summaries remain limited. We developed scGPA, an LLM-assisted workflow system for directional single-cell virtual gene perturbation analysis. METHODS: scGPA starts from raw single-cell RNA sequencing data and performs quality control, normalization, dimensionality reduction, clustering and cell-group selection. It then constructs cell-group-specific wild-type regulatory networks using repeated subsampling, principal component regression (PCR)/Ridge-based network inference and CP tensor denoising. Based on these networks, scGPA simulates dose-aware virtual knockdown of the target gene and applies signed perturbation propagation to estimate the magnitude and direction of downstream transcriptional responses. LLM assistance is used for marker-based cell-type annotation, evidence-guided candidate prioritization and user-facing biological summarization. RESULTS: We benchmarked scGPA across five public Perturb-seq datasets and compared its performance with GEARS, scGPT and a random baseline. The overall correct prediction rate of scGPA was 23.0%, exceeding those of GEARS (20.7%), scGPT (15.1%) and the random baseline (13.6%). These results indicate that scGPA achieved a higher correct prediction rate than the two comparator models and the random baseline. We subsequently evaluated scGPA using a public osteosarcoma single-cell dataset and performed qRT-PCR validation in 143B osteosarcoma cells. Among genes with significant experimental changes, scGPA achieved a directional concordance of 76.9%. When all tested downstream genes were counted, 37.0% were directionally correct, 51.9% showed no significant change and 11.1% changed in the opposite direction. CONCLUSIONS: scGPA provides a practical workflow system for predicting and prioritizing direction-specific downstream transcriptional responses after target-gene perturbation. By integrating single-cell regulatory network inference, signed virtual perturbation and LLM-assisted interpretation, scGPA supports target-gene function inference and downstream mechanistic investigation from single-cell transcriptomic data.

Single-Cell Gene Expression Analysis↗

PubMed1995

A repeated measures approach to the detection of the acute behavioral effects of toluene at low concentrations.

Acute behavioral effects of solvents are frequently the critical parameter considered for the recommendation of exposure limit values. Studies of toluene's acute effects on animal behavior during exposure have not been particularly sensitive; increasing the number of observations at low concentrations and the number of animals studied is a reasonable approach to increasing the ability to detect small acute effects. The effects of toluene (178-3000 ppm) were determined in 12 rats trained to nose poke on a probabilistic schedule of food delivery in a small exposure chamber that was highly ventilated with air or a toluene test atmosphere. Animals served as their own controls and were exposed to toluene twice a week for 2 hr during behavioral evaluation. At least six determinations of the effects of toluene were made at concentrations of 178, 300, and 560 ppm, and at least three determinations at 1000, 1780, and 3000 ppm. Biphasic concentration-effect, time-effect, and concentration-response functions were observed. Rates of nose poking increased in 4 of 12 animals at 178 ppm and in 9 of 12 animals at 300 ppm; all animals were affected at 560 ppm. The concentration at which a 10% rate increase occurred was determined by regression analysis to be 156 ppm with the lower 95% confidence limit or "benchmark" concentration being 116 ppm. Weighted regression analysis produced slightly higher estimates of these parameters, 182 and 157 ppm, respectively, while conventional logistic regression revealed that 10% of animals would be affected at a concentration of 114 ppm with a lower confidence limit of 63 ppm.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2000

Chlorpromazine versus placebo for schizophrenia.

BACKGROUND: Chlorpromazine, formulated in the 1950s, remains a benchmark treatment for those with schizophrenia. OBJECTIVES: To evaluate the effects of chlorpromazine for schizophrenia in comparison to placebo. SEARCH STRATEGY: Electronic searches of Biological Abstracts (1982-1995), The Cochrane Library (1999, Issue 2), The Cochrane Schizophrenia Group's Register (October 1999), EMBASE (1980-1995), MEDLINE (1966-1995), PsycLIT (1974-1995) were undertaken. References of all identified studies were searched for further trial citations. Pharmaceutical companies and authors of trials were contacted. SELECTION CRITERIA: Randomised controlled trials relating to people with schizophrenia, and non-affective serious/chronic mental illness irrespective of mode of diagnosis evaluating chlorpromazine (any dose) versus placebo. Primary outcomes of interest were death, violent behaviours, overall improvement, relapse and satisfaction with care. DATA COLLECTION AND ANALYSIS: Citations and, where possible, abstracts were independently inspected by reviewers, papers ordered, re-inspected and quality assessed. Data were extracted by BT with CA and GA independently checking a 10% sample for reliability. Dichotomous data were analysed using random effects relative risk (RR) and the 95% confidence interval around this was estimated. Where possible the number needed to treat (NNT) or number needed to harm statistics (NNH) were calculated. Continuous data were excluded if more than 50% of people were lost to follow up, but, where possible, weighted mean difference was calculated. Sensitivity analyses have not been undertaken for this version of the review. MAIN RESULTS: Over 1000 electronic records were inspected. The review currently mentions 202 papers in its Excluded Studies section and 45 studies in its Included Studies table. Six papers await assessment. Chlorpromazine reduces relapse over six months to two years (RR 0.65 CI 0.5-0.9, NNT 3 CI 2.5-4) and there is convincing evidence from trials that it promotes a global improvement in a person's symptoms and functioning (RR 0.76 CI 0.7-0.9, NNT 7 CI 5-10) although the placebo response is also considerable (nearly 40%). Fewer people allocated to chlorpromazine leave trials early (RR 0.76 CI 0.6-1.1). There are many adverse effects. Chlorpromazine is clearly sedating (RR 2.4 CI 1.7-3.3, NNH 6 CI 4-8), it increases a person's chances of experiencing acute movement disorders (RR 3.1 CI 1.3-7.6, NNH 24 CI 14-77), parkinsonism (RR 2.6 CI 1.2-5.4, NNH 10 CI 8-16) and fits (RR 2.4 CI 0.4-16). Amongst other things it clearly causes a lowering of blood pressure with accompanying dizziness (RR 1.9 CI 1. 3-2.6, NNH 12 CI 8-22) and considerable increases in weight (RR 4.4 CI 2.1-9, NNH 3 CI 2-5). REVIEWER'S CONCLUSIONS: This review will confirm much that clinicians and recipients of care already know but provides quantification to support clinical impression. Despite the humbling 40% improvement rate in those who were allocated to placebo, chlorpromazine's global position as the 'benchmark' treatment of those with psychoses is not threatened by this review. Chlorpromazine, in common use for nearly half a century, is a well established but imperfect treatment. Judicious use of this best available evidence should lead to better informed decisions both by carers and those with psychotic illnesses.

Antipsychotic Agents↗