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PubMed2002

Quantitative determination of cellulase concentration as distinct from cell concentration in studies of microbial cellulose utilization: analytical framework and methodological approach.

In analyzing microbial cellulose utilization, it would be useful to independently measure the mass concentration of cells and cellulase enzymes. Such measurements would allow investigation of the allocation of cellular resources between synthesis of cells and cellulase, in vivo cell- and cellulase-specific cellulose hydrolysis rates, and bioenergetics. Methodological protocols are not established for independent determination of cell and cellulase concentrations for the common case in which a substantial fraction of cellulase is attached to the cell surface. Alternative analytical approaches by which to develop such protocols are examined from the perspective of error minimization. For cell concentration measurement, acceptable accuracy is expected when the concentrations of a cell-specific component (e.g., DNA) is determined or when total protein is determined in conjunction with a measurement specific to cellulase. For cellulase concentration measurement, acceptable accuracy is expected when a measurement specific to cellulase such as ELISA is used. Several analytical approaches are rejected based on large expected errors.

Bacteria↗
PubMed1990

In vivo oxidative DNA damage: measurement of 8-hydroxy-2'-deoxyguanosine in DNA and urine by high-performance liquid chromatography with electrochemical detection.

HPLC with electrochemical detection is a highly sensitive and selective method for detecting the oxidatively modified DNA residue oh8dG. By this method, the detection of oh8dG from DNA and urine offers a powerful approach for assessing in vivo oxidative damage. Application of this technique to the detection of oh8dG from DNA permits the quantitation of the steady-state levels of this oxidatively modified deoxynucleoside and overcomes the detection problems associated with the extremely low levels present in DNA. In addition, the selectivity gained by this detection method eliminates the problem of separating the signal for oh8dG from normal deoxynucleosides. The quantitation of oh8dG in urine complements the measurement of oh8dG in DNA by estimating cumulative oxidative DNA damage in the body. In addition, the urinary assay provides a noninvasive means of measuring this type of damage in laboratory animals and human populations. Thus, an individual animal or human subject may be monitored over time, possibly under various prooxidant conditions, using oh8dG as a sensitive marker for oxidative DNA damage. This analytical approach may allow one to estimate the exposure of an individual to prooxidant conditions associated with lifestyle, genetic predisposition, degenerative diseases, and environmental toxins.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1998

Intention-to-treat vs. on-treatment analyses of clinical trial data: experience from a study of pyrimethamine in the primary prophylaxis of toxoplasmosis in HIV-infected patients. ANRS 005/ACTG 154 Trial Group.

Randomized clinical trials analyzed by the intent-to-treat approach provide unbiased comparisons among treatment groups. To avoid dilution of treatment effect, many people also perform an analysis by treatment actually received, although this method may introduce bias into the results. This paper presents several approaches used for analyzing data of a recent trial and the difficulties encountered in interpreting the results of each approach. The ANRS 005/ACTG 154 Study was a double-blind, placebo-controlled, randomized, international (French, U.S., and Spanish) multicenter trial designed to assess the effectiveness of pyrimethamine for the primary prophylaxis of cerebral toxoplasmosis (CT) in HIV-infected patients with advanced immunodeficiency. In the intention-to-treat analysis, the cumulative probability of CT at 1 year did not differ significantly between the pyrimethamine arm (11.9%) and the placebo arm (13.1%), Hazard Ratio (HR) = 0.94 (95% Confidence Interval (CI) = 0.62-1.42), whereas an on-treatment analysis resulted in a significant difference: 4.2% in the pyrimethamine arm and 12.4% in the placebo arm, HR = 0.44 (95% CI = 0.24-0.80). The data showed a significant interaction between compliance and treatment outcome; and side effects were more frequently cited as reasons for compliance violations in the pyrimethamine group. Several different analytic approaches (censoring data at the time patients discontinued the study medication only for selected reasons) failed to explain the disparity between the estimation of effect of pyrimethamine by the intention-to-treat and on-treatment analyses. This experience led us to believe that comparing the results of both analyses was the best method to convince clinicians that intention-to-treat was the only interpretable analysis. We were concerned that even if pyrimethamine had a beneficial effect, it was very difficult (1) to quantify and (2) to apply to clinical practice unless one could predict the occurrence of study drug discontinuation for each patient at the time of treatment assignment. Although exploratory analyses may yield clinically relevant information and useful clarifications in the evaluation of treatments, intention-to-treat remains the only interpretable analysis of clinical trials.

AIDS-Related Opportunistic Infections↗
PubMed2004

Clinical trial methodology and clinical cohorts: the importance of complete follow-up in trials evaluating the virological efficacy of anti-HIV medicines.

PURPOSE OF REVIEW: It has been common practice in randomized trials of HIV medicines to classify switches away from the original therapy as failures in analyses of virological effect, in line with an HIV-RNA measurement above a given level of quantification. This approach precludes the ability to identify the possible effects of a given therapy on those of a subsequent therapy. This review explores whether there have been changes in the reporting of randomized trials since the importance of continuous follow-up throughout the study period was initially raised 2 years ago. RECENT FINDINGS: Follow-up is still likely to be discontinued at a premature switch from study medication in a large number of the randomized trials published in 2002-2003. However, some studies, all initiated by investigators, did follow patients throughout the study period. In three of the studies, the proportions of patients with virological failure assessed with and without data after the premature discontinuation of randomized therapy could be elicited. Substantial differences were seen in the comparisons of two highly active antiretroviral therapy regimens according to the choice of analytical approach. In all three studies significant differences were observed between the regimens according to one approach, but not to the other. SUMMARY: The notation of treatment switch equals failure leads to an imprecise measurement of virological effect, and complete follow-up throughout the study period should be strongly encouraged, thus enabling several supplementary analyses of the virological effect of the treatment strategies being compared.

Anti-HIV Agents↗
PubMed2003

An intent-to-treat method for enhancing analysis of clinical trials with rescue medication: a mixed-model approach.

An intent-to-treat (IT) analysis includes all observed data, even those obtained after the primary treatment assignment is changed or rescue treatment is substituted. The so-called "pragmatic" approach accounts for this type of treatment change or rescue treatment. The advantage of the pragmatic approach to IT analysis is that the timing and duration of the rescue treatment can be included in the analysis with mixed-effect modeling, which estimates the difference between the randomized treatment arms while adjusting for the use (timing and duration) of the subsequent treatment. We illustrate the inclusion of information on rescue treatment timing and duration in the analysis of a two-arm randomized clinical trial comparing antidepressant medications in an elderly depressed population. In this study, the randomized treatments are found to be similar. This enhanced analysis, where information about rescue treatment is implicitly added in the model, corroborates our previous two-piece spline analysis, where information about rescue treatment was not included. In addition, a significant drug by rescue interaction indicates a differential effect of the timing of rescue treatment between the two treatments. This analytic approach illustrates the importance of collecting and incorporating data after rescue, including the timing of rescue.

Data Interpretation, Statistical↗
PubMed2002

A qualitative analysis of medication use variance reports.

BACKGROUND: This report of a process change utilized a qualitative approach to data analysis to improve medication use safety in a large hospital. The two goals were to design a strategy to analyze the qualitative data and to use that strategy to uncover previously unclassified medication use variance patterns that could be prevented. A multidisciplinary team performed the analysis in an effort to improve the quality and yield of the approach. METHODS: All medication use variance, incident, and event reports from Yale-New Haven Hospital during April-June 2000 were collected (N = 264). A 20% random sample of the reports was distributed to a five-member evaluation group (a pharmacist, two nurses, and two physicians) for independent qualitative analysis and coding. An initial coding framework was produced using a consensus process. This coding framework was applied to another sample, and the consensus and coding processes were repeated until no new domains were identified. RESULTS: Ten general medication use variance domains were determined. In addition, 21 subdomains among the various general domains were determined. DISCUSSION: Utilizing a multidisciplinary team and a qualitative strategy of analysis improved patient safety efforts. This combination led to the discovery of new variance domains, causes, and opportunities to intervene and ultimately prevent medication use variances. This analytic approach is widely applicable, adaptable, and dynamic. The design and results of this report improve on a strictly quantitative approach to medication use variance analysis. The approach employed by this report will be used to improve medication use safety within the Yale-New Haven Health System.

Adverse Drug Reaction Reporting Systems↗
PubMed1999

Capillary electrophoresis sodium dodecyl sulfate nongel sieving analysis of a therapeutic recombinant monoclonal antibody: a biotechnology perspective.

With the increasing interest in the therapeutic use of recombinant monoclonal antibodies (rMAbs), a generic analytical approach for the analysis of size-based rMAb variants is desired. Such a method using capillary electrophoresis (CE) with laser-induced fluorescence detection is described. The assay was developed as a replacement for silver-stained SDS-PAGE and was validated according to the guidelines of the International Committee on Harmonization for use in routine lot release testing of a rMAb pharmaceutical. In this assay, the rMAb solution is first derivatized with a neutral fluorophore, e.g., 5-carboxytetramethylrhodamine succinimidyl ester. The labeled sample is then incubated with SDS, and the SDS-protein complexes are then separated by CE using a hydrophilic polymer as a sieving matrix. The precolumn labeling conditions described in this study allowed the detection of rMAb at a low-nanomolar concentration (9 ng/mL), with no apparent loss in resolution or changes to the distribution of rMAb analyte species, when compared to an unlabeled sample. In addition, the traditional practice of heating proteins at elevated temperatures in the presence of SDS to facilitate SDS-protein binding resulted in the generation of significant levels of rMAb fragmentation, and alternative conditions to minimize this artifact are discussed. Illustrations of the uses of this assay in monitoring consistency of bulk manufacture of a protein pharmaceutical, and in providing a size-based separation of product-related variants, as well as nonproduct impurities are shown. In brief, the assay described in this paper demonstrated comparable resolution and sensitivity to silver-stained SDS-PAGE but offered the advantages of enhanced precision and robustness, speed, ease of use, and on-line detection.

Antibodies, Monoclonal↗
PubMed2004

Typologies of drug dependence: comparative validity of a multivariate and four univariate models.

Data from a longitudinal cohort study were used to directly compare the concurrent and predictive validity of four univariate typologic approaches with a multivariate approach in subtyping drug dependence. The four univariate typologies were based upon: (a) age-of-onset of drug abuse/dependence, (b) presence of drug abuse in first-degree relatives, (c) presence of antisocial personality disorder, and (d) sex. The multivariate typologic approach was based on indices of vulnerability, chronicity, consequences, and psychopathology, yielding the Type A/B dichotomy first demonstrated in alcohol dependence. Subtypes generated from the univariate typologies were then each compared with the multivariate typology on measures of concurrent and predictive validity, and the strength of association was compared statistically. There was evidence of significantly greater concurrent validity of the Type A/B typology compared with the univariate typologies across all the domains of validation (risk, substance use, psychopathology, personality, and overall functioning). The multivariate typology also fared better than the univariate ones in all three domains on which predictive validity was evaluated: substance use, psychopathology, and overall functioning, as well as the degree of change in several composite scores (drug, medical, legal, and psychiatric) and the global psychiatric symptom index. This direct method of comparison seemed to demonstrate the superior validity of the multivariate cluster-analytic approach over the univariate approaches to classifying subjects with drug dependence.

Age Factors↗
PubMed2004

Rat myocellular and perimysial intramuscular triacylglycerol: a histological approach.

PURPOSE: There is controversy as to the use of intramuscular triacylglycerol (IMTAG) during exercise and to whether endurance training increases its utilization, despite the various methodologies used to address these questions. We used a histological-morphometrical approach to study the relative contribution of the two compartments of IMTAG storage, intramyocellular, and perimysial adipocytes, during exercise in sedentary and endurance-trained rats. METHODS: After osmium impregnation, the soleus (SOL) and gastrocnemius (GAS) were studied under light and electron microscopy. IMTAG content (after Triton WR1339 treatment or not) and 14C-oleate incorporation into the muscles were studied. RESULTS: In GAS, training, but not exercise alone, decreased extramyocellular lipid (P < 0.001 vs sedentary), an effect not found for SOL. Both muscles presented reduced lipid inclusion number (P < 0.001) and area (P < 0.05), immediately after exercise in sedentary and trained rats. For SOL, a greater number (P < 0.001 vs sedentary) of inclusions was found 24 h after exercise in trained rats. Triton WR1339 treatment decreased IMTAG content 12 h after exercise in SOL (but not in GAS), in sedentary (33%), and trained rats (52%). CONCLUSIONS: The multi-analytical approach adopted allowed the discernment between the IMTAG compartments and provided evidence for an effect of training upon storage of lipid in perimysial adipocytes in rat gastrocnemius, as well as clearly showed that the IMTAG mobilized during submaximal exercise in sedentary and trained rats derives from intramyocellular lipid, both in SOL and GAS. Moreover, the reposition of these stores 12 h after exercise was shown to be different in GAS and SOL, as plasma triacylglycerol clearly contributed to the process only in the latter, possibly reflecting the differences in lipoprotein lipase activity in the muscles reported by others.

Adipocytes↗
PubMed2005

Wave transport in two-dimensional random media: the ballistic to diffusive transition and the extrapolation length.

By using a first-principles approach based on the Bethe-Salpeter equation, we study the behavior of wave propagation through a two-dimensional random slab as a function of thickness, L , in the region where L is much smaller than the localization length. A general two-dimensional vertex function for the ladder diagrams is derived from the Ward identity. We calculate both the static and the time-resolved transmitted intensities as functions of L/l , where l is the mean free path. When L is comparable to l , we study the ballistic to diffusive transition. A sharp crossover is observed when L(c) approximately = 6l, which is significantly larger than the crossover thickness of L(c) approximately = 3l found in three dimensions. When L>>l , we obtain the extrapolation length in two dimensions, i.e., z2De approximately = 0.82l, which is noticeably larger than the previously used value of z2De = pi/4 obtained by an analytical approach.

Journal Article↗
PubMed1998

Usefulness of the prognostic inflammatory and nutritional index (PINI) in hospitalized elderly patients.

The prognostic inflammatory and nutritional index (PINI) is a simple scoring system of overall health which aggregates two blood markers of inflammatory (C-reactive protein and alpha(1)-acid glycoprotein) and of nutritional (albumin and transthyretin) states. This study was undertaken with a view to evaluate, in comparison to currently used predictive approaches, the potential usefulness of PINI to forecast hospital mortality and outcome of patients hospitalized in an acute geriatric unit. 1,066 elderly patients, aged 82.7 +/- 6.6 years and fulfilling inclusion criteria, were enrolled in the study. Logistic regression analysis and calculation of relative risk (RR) were carried out for epidemiological data with a cut-off value of 25 for PINI. Immediate mortality (7.9%) of admissions) was predicted by PINI > or = 25 (RR = 4.34). Only 387 patients (36.3%) could rejoin their residence location (home or family). A sizeable proportion of acute patients (55.8%) failed to recover and/or developed diseased states requiring chronic care management. Incapacity to return home was predicted by PINI > or = 25 (RR = 2.04). Hypoalbuminaemia < or = 30 g/L was not found a predictor of mortality but was associated with total disability (RR = 9.08). The optimal PINI cut-off value to predict mortality was calculated at 8.8 using the ROC analytic approach. We conclude that the PINI formula is helpful to predict both nearest lethality and chronic institutionalization. This scoring system should take a place within the battery of tests used to identify and to follow up acutely ill elderly patients at risk of major complications.

Aged↗
PubMed2005

Analysis of incomplete quality of life data in advanced stage cancer: a practical application of multiple imputation.

This paper presents a practical approach to analyzing incomplete quality of life (QOL) data that contains non-ignorable dropouts in patients with advanced non-small-cell lung cancer (NSCLC). QOL scores for the physical domain at baseline and at the end of the first and second courses of chemotherapy were compared between two treatment groups in a phase III trial. One hundred and 103 eligible patients were randomized to receive cisplatin and irinotecan (CPT-P) or cisplatin and vindesine, respectively; of those two groups, 83 and 85, respectively, completed a QOL questionnaire at least at baseline. A multiple imputation incorporating auxiliary QOL variables was implemented as one of alternatives of sensitivity analyses; these were complete case, available case, and pattern mixture analyses. Although larger sensitivity to missing data was found for CPT-P treatment, none of the alternative analyses demonstrated a significant difference in estimated slopes over time between the groups. This study presents an analytical approach for dealing with the complex problem of missing QOL data. It must be noted, however, that the validity of the multiple imputation method we present is not certain unless we can specify sufficiently informative auxiliary variables to ensure the conversion of non-ignorable missingness to ignorable.

Aged↗
PubMed2001

Tailoring bioanalysis for PK studies supporting drug discovery.

Over the last years, there has been an exponentially growing need and interest to bring pharmacokinetic expertise into discovery. In order to allow a multidisciplinary selection and a higher attrition rate, both the in vivo and in vitro pharmacokinetic parameters of an ever increasing number of tentative new chemical entities are evaluated in an earlier phase of Drug Discovery. A higher attrition rate at the beginning of the pipeline should result in a lower attrition rate at a later stage in development. In this process, the bioanalytical laboratory has become increasingly important. Analytical strategies needed to be adapted to cope with novel experimental designs such as cassette dosing, cassette analysis or 96-well techniques. At the same time, HT-synthesis programs surfaced a broader variety of chemical classes to be investigated, disfavoring further generalization of analytical approaches. Progress in lab automation, improved chromatographic techniques and the proliferation of LC-MS/MS enabled the analyst to deal with these challenges much faster and with a higher level of confidence. Quality standards regarding method development and method validation, setting the boundaries for more than a decade, needed to be titrated to reach an optimal balance between speed and quality. This review will give an illustrative overview of the bioanalytical techniques and strategies used to support Drug Discovery, together with some pitfalls related to the overzealous use of new techniques.

Chemistry Techniques, Analytical↗
PubMed1993

Old data, new interpretation: a re-analysis of Sir Aubrey Lewis' M.D. thesis.

Sir Aubrey Lewis studied 61 depressives in considerable detail, principally cross-sectionally but also by reviewing progress. He concluded that he could find no qualitative distinctions between the depressed patients and thus established himself as a strong and influential advocate of the unitary view of depression (i.e. that depression varies dimensionally, not categorically). Subsequently, Kiloh & Garside (proponents of the binary view of two depressive 'types') coded the Lewis data and undertook a principal components analysis. They claimed success in distinguishing 'endogenous' and 'neurotic' depressive types within Lewis' sample. In this paper we re-analyse the data set using both a latent class categorical approach and mixture analyses. We suggest that any demonstration of sub-types was limited by relative homogeneity of the sample (in that up to 80% had probable or possible psychotic conditions), and by Lewis rating a number of important features (e.g. delusions) dimensionally rather than categorically. Nevertheless, we identify one categorical class (essentially an agitated psychotic depressive condition) and a residual (presumably heterogeneous) class. The presence of those two classes was supported by demonstrating bimodality in composite scores derived from the fourteen differentiating clinical features (and not evident when all clinical features were considered), and formally confirmed by mixture analyses. Membership of the categorical class was determined principally by psychotic features (delusions and hallucinations) and by objectively-judged psychomotor disturbance, and we consider the nature of that 'class'. Lewis' data set is unusual (in having self-report and observationally rated data), and historically important in demonstrating that conclusions may depend on the choice of variables examined and analytical approaches.

Academic Dissertations as Topic↗
PubMed2003

Methods for studying synaptosomal copper release.

Cu is thought to play an important role in the pathogenesis of several neurodegenerative diseases, such as Wilson's, Alzheimer's, and probably in prion protein diseases like Creutzfeld-Jakob's disease. Until now, no method existed to determine the concentration of this cation in vivo. Here, we present two possible approaches combined with a critical comparison of the results. The successful use of fluorescent ligands for the determination of Ca2+-concentrations in recent years encouraged us to seek a fluorophore which specifically reacts to Cu2+ and to characterize it for our purposes. We found that the emission of TSPP (tetrakis-(4-sulfophenyl)porphine) at an emission wavelength of 645 nm is in vitro highly specific to Cu2+ (apparent dissociation constant Kd=0.43 +/- 0.07 microM at pH 7.4). It does not react with the most common divalent cations in the brain, Ca2+ and Mg2+, unlike most of the other dyes examined. In addition, Zn2+ quenches TSPP fluorescence at a different emission wavelength (605 nm) with a Kd of 50 +/- 2.5 microM (pH 7.0). With these findings, we applied the measurement of Cu with TSPP to a biological system, showing for the first time in vivo that there is release of copper by synaptosomes upon depolarisation. Our findings were validated with a completely independent analytical approach based on ICP-MS (inductively-coupled-plasma mass-spectrometry).

Animals↗
PubMed1998

Correction for non-compliance in equivalence trials.

In randomized trials comparing a new therapy to standard therapy, the sharp null hypothesis of equivalent therapeutic efficacy does not imply the intent-to-treat null hypothesis of equal outcome distributions in the two-treatment arm if non-compliance is present. As a consequence, the development of analytic methods that adjust for non-compliance is of particular importance in equivalence trials comparing a new therapy to standard therapy. This paper provides, in the context of equivalence trial, a unified overview of various analytic approaches to correct for non-compliance in randomized trials. The overview focuses on comparing and contrasting the plausibility, robustness, and strength of assumptions required by each method and their programming and computational burdens. In addition, several new structural (causal) models are introduced: the coarse structural nested models, the non-nested marginal structural models and the continuous-time structural nested models, and their properties are compared with those of previously proposed structural nested models. The fundamental assumption that allows us to correct for non-compliance is that the decision whether or not to continue to comply with assigned therapy at time t is random (that is, ignorable or explainable) conditional on the history up to t of measured pre- and time-dependent post-randomization prognostic factors. In the final sections of the paper, we consider how the consequences of violations of our assumption of conditionally ignorable non-compliance can be explored through a sensitivity analysis. Finally, the analytic methods described in this paper can also be used to estimate the causal effect of a time-varying treatment from observational data.

Algorithms↗
PubMed2006

An approach for developing a national estimate of waterborne disease due to drinking water and a national estimate model application.

In this paper, the US Environmental Protection Agency (EPA) presents an approach and a national estimate of drinking water related endemic acute gastrointestinal illness (AGI) that uses information from epidemiologic studies. There have been a limited number of epidemiologic studies that have measured waterborne disease occurrence in the United States. For this analysis, we assume that certain unknown incidence of AGI in each public drinking water system is due to drinking water and that a statistical distribution of the different incidence rates for the population served by each system can be estimated to inform a mean national estimate of AGI illness due to drinking water. Data from public water systems suggest that the incidence rate of AGI due to drinking water may vary by several orders of magnitude. In addition, data from epidemiologic studies show AGI incidence due to drinking water ranging from essentially none (or less than the study detection level) to a rate of 0.26 cases per person-year. Considering these two perspectives collectively, and associated uncertainties, EPA has developed an analytical approach and model for generating a national estimate of annual AGI illness due to drinking water. EPA developed a national estimate of waterborne disease to address, in part, the 1996 Safe Drinking Water Act Amendments. The national estimate uses best available science, but also recognizes gaps in the data to support some of the model assumptions and uncertainties in the estimate. Based on the model presented, EPA estimates a mean incidence of AGI attributable to drinking water of 0.06 cases per year (with a 95% credible interval of 0.02-0.12). The mean estimate represents approximately 8.5% of cases of AGI illness due to all causes among the population served by community water systems. The estimated incidence translates to 16.4 million cases/year among the same population. The estimate illustrates the potential usefulness and challenges of the approach, and provides a focus for discussions of data needs and future study designs. Areas of major uncertainty that currently limit the usefulness of the approach are discussed in the context of the estimate analysis.

Communicable Diseases↗
PubMed1994

Comparative activity of human carcinogens and NTP rodent carcinogens in the mouse bone marrow micronucleus assay: an integrative approach to genetic toxicity data assessment.

The mouse bone marrow micronucleus (MN) assay holds a key position in all schemes for detecting potential human carcinogens and mutagens. It was therefore of concern when Shelby et al. reported that only 5 of 25 rodent carcinogens defined by the U.S. NTP were positive in the assay. Further, each of these positive responses was weak and indistinguishable from the 4 positive responses observed among the 24 NTP noncarcinogens tested. To focus these findings, the activity in the MN assay of 26 human carcinogens, 6 reference rodent genotoxins, and the 9 NTP chemicals positive in the MN assay have been displayed in a common format. This involved plotting the minimum positive dose level (expressed as mumole/kilogram) and the maximum fold-increase in micronucleated polychromatic erythrocytes frequency observed at any dose level. By displaying the high sensitivity of the micronucleus assay to the reference human and rodent genotoxins, this analysis emphasizes the weakness in the MN assay responses given by the NTP carcinogens reported by Shelby et al. This, in turn, poses questions about the intrinsic hazard of this selection of NTP rodent carcinogens. Using fotemustine and vitamin C as models of a toxic and a nontoxic chemical known to be active in the MN assay, this analysis describes a method by which their relative potential human hazard can be distinguished (a synthetic, as opposed to an analytical approach to data assessment). The possibility that some weak responses observed in the MN assay at elevated dose levels may be stress induced is considered.

Animals↗