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J Kleiner

Publications and source records attributed to J Kleiner.

At least 19 recordsLinked to original sources
PubMed2006

Risk assessment of substances that are both genotoxic and carcinogenic report of an International Conference organized by EFSA and WHO with support of ILSI Europe.

The European Food Safety Authority (EFSA) and the World Health Organization (WHO), with the support of the International Life Sciences Institute, European Branch (ILSI Europe), organized an international conference on 16-18 November 2005 to discuss how regulatory and advisory bodies evaluate the potential risks of the presence in food of substances that are both genotoxic and carcinogenic. The objectives of the conference were to discuss the possible approaches for risk assessment of such substances, how the approaches may be interpreted and whether they meet the needs of risk managers. ALARA (as low as reasonably achievable) provides advice based solely on hazard identification and does not take into account either potency or human exposure. The use of quantitative low-dose extrapolation of dose-response data from an animal bioassay raises numerous scientific uncertainties related to the selection of mathematical models and extrapolation down to levels of human exposure. There was consensus that the margin of exposure (MOE) was the preferred approach because it is based on the available animal dose-response data, without extrapolation, and on human exposures. The MOE can be used for prioritisation of risk management actions but the conference recognised that it is difficult to interpret it in terms of health risk.

Animals↗
PubMed2005

The threshold of toxicological concern concept in risk assessment.

The concept that "safe levels of exposure" for humans can be identified for individual chemicals is central to the risk assessment of compounds with known toxicological profiles. The Threshold of Toxicological Concern (TTC) is a concept that refers to the establishment of a level of exposure for all chemicals, whether or not there are chemical-specific toxicity data, below which there would be no appreciable risk to human health. The concept proposes that a low level of exposure with a negligible risk can be identified for many chemicals, including those of unknown toxicity, based on knowledge of their chemical structures. The present paper aims to describe the history of the TTC principle, its use to date, its potential future applications and the incorporation of the TTC principle in the Risk Assessment paradigm.

Animals↗
PubMed2004

Structure-based thresholds of toxicological concern (TTC): guidance for application to substances present at low levels in the diet.

The threshold of toxicological concern (TTC) is a pragmatic risk assessment tool that is based on the principle of establishing a human exposure threshold value for all chemicals, below which there is a very low probability of an appreciable risk to human health. The concept that there are levels of exposure that do not cause adverse effects is inherent in setting acceptable daily intakes (ADIs) for chemicals with known toxicological profiles. The TTC principle extends this concept by proposing that a de minimis value can be identified for many chemicals, in the absence of a full toxicity database, based on their chemical structures and the known toxicity of chemicals which share similar structural characteristics. The establishment and application of widely accepted TTC values would benefit consumers, industry and regulators. By avoiding unnecessary toxicity testing and safety evaluations when human intakes are below such a threshold, application of the TTC approach would focus limited resources of time, cost, animal use and expertise on the testing and evaluation of substances with the greatest potential to pose risks to human health and thereby contribute to a reduction in the use of animals. An Expert Group of the European branch of the International Life Sciences Institute-ILSI Europe-has examined the TTC principle for its wider applicability in food safety evaluation. The Expert Group examined metabolism and accumulation, structural alerts, endocrine disrupting chemicals and specific endpoints, such as neurotoxicity, teratogenicity, developmental toxicity, allergenicity and immunotoxicity, and determined whether such properties or endpoints had to be taken into consideration specifically in a step-wise approach. The Expert Group concluded that the TTC principle can be applied for low concentrations in food of chemicals that lack toxicity data, provided that there is a sound intake estimate. The use of a decision tree to apply the TTC principle is proposed, and this paper describes the step-wise process in detail. Proteins, heavy metals and polyhalogenated-dibenzodioxins and related compounds were excluded from this approach. When assessing a chemical, a review of prior knowledge and context of use should always precede the use of the TTC decision tree. The initial step is the identification and evaluation of possible genotoxic and/or high potency carcinogens. Following this step, non-genotoxic substances are evaluated in a sequence of steps related to the concerns that would be associated with increasing intakes. For organophosphates a TTC of 18microg per person per day (0.3 microg/kg bw/day) is proposed, and when the compound is not an OP, the TTC values for the Cramer structural classes III, II and I, with their respective TTC levels (e.g. 1800, 540 and 90 microg per person per day; or 30, 9 and 1.5 microg/kg bw /day), would be applied sequentially. All other endpoints or properties were shown to have a distribution of no observed effect levels (NOELs) similar to the distribution of NOELs for general toxicity endpoints in Cramer classes I, II and III. The document was discussed with a wider audience during a workshop held in March 2003 (see list of workshop participants).

Animals↗
PubMed2003

Guidance for the safety assessment of botanicals and botanical preparations for use in food and food supplements.

There is a growing interest by both consumers and industry for the development of food products with 'functional' properties, or health benefits. These products may take the form of dietary supplements or of foods. The health benefits are given by particular ingredients, and in many cases these are derived from botanicals. The variety of plants providing these functions is large, ranging from staple food sources such as cereals, fruits and vegetables, to herbals as used in traditional medicine. The food or ingredient conferring health properties may consist of the plants themselves, extracts thereof, or more purified components. The scientific literature is abundant with articles not only on the beneficial properties, but also on possible adverse health effects of plants and their components. The present report discusses the data required to determine the safe use of these types of ingredients, and provides advice on the development of risk assessment strategies consistent with due diligence under existing food regulations. Product specifications, composition and characterisation of standardised and authentic materials, documented history of use and comparison to existing products (taking into account the effect of industrial processing), description of the intended use and consequent exposure are highlighted as key background information on which to base a risk evaluation. The extent of experimental investigation required, such as in vitro, animal, and/or human studies, depends on the adequacy of this information. A decision tree is presented as an aid to determine the extent of data requirements based on product comparison. The ultimate safety in use depends on the establishment of an adequate safety margin between expected exposure and identified potential hazards. Health hazards may arise from inherent toxicities or contaminants of the plant materials, including the mechanism of the intended beneficial effect. A lower safety margin may therefore be expected than for food ingredients or additives where no physiological effects are intended. In rare cases, post launch monitoring programmes may be envisaged to confirm expected exposures and adequacy of the safety margin. This guidance document was elaborated by an expert group of the Natural Toxin Task Force of the European Branch of the International Life Sciences Institute--ILSI Europe and discussed with a wider audience of scientists at a workshop held on 13-15 May 2002 in Marseille, France.

Animals↗
PubMed2002

Neuropsychological impairment in veterans who are HIV-positive.

The purpose of this study was to compare the neuropsychological functioning of 12 veterans who were HIV-positive to 21 age-matched veterans who were HIV-negative. Consistent with expectations, the HIV-positive group was found to perform more poorly in areas related to attention and concentration, immediate and delayed verbal recall, immediate and delayed visual recall, visual learning, and tasks requiring psychomotor speed, while a number of language tasks were left intact. This was similar to dysfunction often seen in HIV-related dementia cases. However, this group was also significantly more impaired in confrontation naming, planning, mental calculations, and abstract thought when compared to the HIV-negative group. Comorbid substance abuse found in the majority of our HIV-positive subjects was thought to contribute to the HIV-related dysfunction.

AIDS Dementia Complex↗
PubMed2002

Verbal learning and visuomotor attention in Alzheimer's disease and geriatric depression.

We compared the verbal learning and visuomotor attention of 34 Alzheimer's patients and 18 depressive patients. Verbal learning was assessed using The Hopkins Verbal Learning Test--Revised (HVLT--R); visuomotor attention was assessed using the Trail Making Test (TMT). The Alzheimer's patients had significantly lower scores on immediate and delayed recall of a word list. There was a nonsignificant trend in this group toward a fewer number of true positives and a greater number of false positives. Alzheimer's patients were significantly slower on Trails A, with a nonsignificant trend toward slower performance on Trails B. No difference was observed in accuracy of attentional processing. The results are discussed in terms of other factors, such as stage of cognitive decline, which might have influenced the findings.

Aged↗
PubMed2001

Safety considerations of DNA in food.

Recombinant DNA techniques are capable of introducing genetic changes into food organisms that are more predictable than those introduced through conventional breeding techniques. This review discusses whether the consumption of DNA in approved novel foods and novel food ingredients derived from genetically modified organisms (GMOs) can be regarded as being as safe as the consumption of DNA in existing foods. It concludes that DNA from GMOs is equivalent to DNA from existing food organisms that has always been consumed with human diets. Any risks associated with the consumption of DNA will remain, irrespective of its origin, because the body handles all DNA in the same way. The breakdown of DNA during food processing and passage through the gastrointestinal tract reduces the likelihood that intact genes capable of encoding foreign proteins will be transferred to gut microflora. The review does not specifically address food safety issues arising from the consumption of viable genetically modified microorganisms but it shows that the likelihood of transfer and functional integration of DNA from ingested food by gut microflora and/or human cells is minimal. Information reviewed does not indicate any safety concerns associated with the ingestion of DNA per se from GMOs resulting from the use of currently available recombinant DNA techniques in the food chain.

Consumer Product Safety↗
PubMed1999

Nimodipine treatment of an adolescent with ultradian cycling bipolar affective illness.

This is a single case report of an open trial of nimodipine, a dihydropyridine-type calcium antagonist, in the treatment of a 13-year-old boy with refractory, ultradian rapid cycling, bipolar disorder type I. Prior clinical trials with calcium channel blockers in adults with ultrarapid cycling affective disorder supported an empirical trial of nimodipine for treatment of ultradian rapid cycling in this adolescent. Severity of mania and depression were rated before and after nimodipine therapy. A marked decrease in rapid, repeated, and significant mood changes was clinically observed and measured by standardized scales after 9 days of nimodipine 180 mg daily. No adverse effects were noticed. Remission persisted with continued treatment at 36-month follow-up. Medication response was partially attributed to adjunctive therapy with levothyroxine. Implications of treatment benefit are discussed in the context of novel pharmacotherapies for refractory bipolar disorder. These findings are preliminary and do not provide sufficient basis to recommend nimodipine as the treatment of choice in adolescents with ultradian cycling bipolar disorder, but suggest that controlled studies may be indicated.

Activity Cycles↗
PubMed1999

Lithium-induced subclinical hypothyroidism: review of the literature and guidelines for treatment.

BACKGROUND: This review addresses the definition, prevalence, etiology, and clinical significance of lithium-associated subclinical hypothyroidism and offers guidelines for evaluation and treatment of this condition. DATA SOURCES: MEDLINE was used to search all articles written in English from 1964-present that included the words lithium and thyroid; lithium and subclinical hypothyroidism; mood and thyroid function; and bipolar illness and thyroid function. STUDY FINDINGS: Lithium interferes with thyroid metabolism and increases the incidence of overt and subclinical hypothyroidism. Subclinical hypothyroidism may be associated with the presence of somatic and neuropsychiatric symptoms and interfere with treatment responsiveness. CONCLUSION: A careful assessment of thyroid function is recommended prior to initiating lithium treatment and during maintenance treatment. Recommendations regarding the threshold for initiation of thyroxine supplementation in patients with lithium-associated subclinical hypothyroidism are discussed in relationship to the degree of detrimental effects potentially associated with thyroid dysfunction.

Bipolar Disorder↗
PubMed1998

Interobserver reliability of detecting lumbar intervertebral disc high-intensity zone on magnetic resonance imaging and association of high-intensity zone with pain and anular disruption.

STUDY DESIGN: Retrospective analysis of a spine imaging center's records of patients with chronic low back pain referred by tertiary care facilities. OBJECTIVES: 1) To assess the interobserver reliability of detecting lumbar intervertebral disc high-intensity zone on T2-weighted magnetic resonance imaging, and 2) to assess the relation between high-intensity zone and discography or post-computed tomography in symptomatic patients with low back pain. SUMMARY OF BACKGROUND DATA: Two of the three previous studies on this subject found an association between high-intensity zone and the presence of Grade 4 anular disruption with discographic reproduction of patients' exact low back pain. METHODS: Records of patients with low back pain who had undergone lumbar spine discography injection and post-computed tomography from June 1995 to August 1996 were reviewed. Two independent observers were asked to identify the presence of an high-intensity zone from the T12-L1 disc to L5-S1 on T2-weighted magnetic resonance images. With this data, interobserver reliability was assessed with the kappa statistic. Concordant high-intensity zone results were then compared with the Dallas Discogram rating for anular disruption and to patients' subjective pain response to discography injection. With this data, the sensitivity, specificity, and predictive values of high-intensity zone for detecting disc disruption and pain response were calculated. RESULTS: The interobserver reliability for detecting a high-intensity zone in a given disc was fair to good (kappa = 0.57; 95% confidence interval = 0.44, 0.70). The sensitivity of high-intensity zone for detecting Grade 4 anular disruption and exact pain was poor (31%) but its specificity was relatively high (90%). The positive predictive value of a high-intensity zone was low (40%) for a severely disrupted and exactly painful disc. CONCLUSIONS: The interobserver reliability of detecting a high-intensity zone and the positive predictive value of the presence of a high-intensity zone for detecting a severely disrupted and exactly painful disc were much lower than previous studies have shown. The relatively low positive predictive value may be attributable to differences in sample characteristics or procedural variations, or suggest that a high-intensity zone is not indicative of exactly painful internal intervertebral disc disruption.

Adult↗
PubMed1992

Mo et al. reply.

Explore the source record for details and available documents.

Journal Article↗
PubMed1988

Acute stroke therapy trials: problems in patient accrual.

Temple University Hospital participated in a multicenter acute stroke trial but enrolled only one patient out of 192 screened over 2 years; other centers had similar difficulty in patient recruitment. We analyzed our screening data to determine which enrollment criteria created difficulties in recruitment and whether the problem was attributable to any single criterion or to combinations of criteria. Six individual criteria were frequent causes for exclusion; however, greater than 80% of the patients were excluded for multiple reasons. Consequently, modifying or eliminating any single criterion did not appreciably increase patient accrual. Only 17 of 210 possible pairs of criteria occurred with statistically significant frequency (p less than 0.05), and these were most likely random associations. Therefore, only by minimizing the number and stringency of enrollment criteria will patient accrual be at a level that allows the study to be completed in a timely manner with a fiscally reasonable number of centers.

Acute Disease↗
PubMed1981

The effect of reagents that increase membrane fluidity on the activity of 3-hydroxyl-3-methyl glutaryl coenzyme A reductase in the CHO-K1 cell.

The compounds cetyl trimethyl ammonium bromide (CTAB) and ethanol both decrease the order parameter of a spin probe embedded in cholesterol-lecithin liposomes, but CTAB produces lowering of the order parameter comparable to that produced by ethanol at a 10,000-fold lower concentration. Treatment of CHO-K1 cells with CTAB or ethanol at concentrations that produce comparable increases of membrane fluidity produce to 2- to 3-fold increase of microsomal membrane cholesterol to phospholipid ratio and a 2- to 3-fold increase of the activity of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Cells treated with CTAB or ethanol show a progressively decreasing capacity to accumulate alpha-aminoisobutyric acid with increasing drug treatment, but cells pre-treated with CTAB are relatively resistant to the effects of CTAB on alpha-aminoisobutyrate transport. The increase in HMG-CoA reductase by CTAB or ethanol is not observed when these compounds are added directly to cell extracts but, rather, is only observed after 8 hours or exposure of intact cells to these drugs. Actinomycin D and cycloheximide treatment prevent the increase in enzyme activity, and the increase is also blocked in a regulatory mutant of the CHO-K1 cell with permanently repressed HMG-CoA reductase activity. These data are consistent with a homeoviscous adaptation mechanism in the CHO-K1 cell, in which increased activity of HMG-CoA reductase, through a process requiring RNA and protein synthesis, compensates for conditions that increase membrane fluidity by increased cellular cholesterol biosynthesis and cholesterol to phospholipid ratio.

Aminoisobutyric Acids↗
PubMedDate not supplied

Assessment of intake from the diet.

Exposure assessment is one of the key parts of the risk assessment process. Only intake of toxicologically significant amounts can lead to adverse health effects even for a relatively toxic substance. In the case of chemicals in foods this is based on three major aspects: (i) how to determine quantitatively the presence of a chemical in individual foods and diets, including its fate during the processes within the food production chain; (ii) how to determine the consumption patterns of the individual foods containing the relevant chemicals; (iii) how to integrate both the likelihood of consumers eating large amounts of the given foods and of the relevant chemical being present in these foods at high levels. The techniques used for the evaluation of these three aspects have been critically reviewed in this paper to determine those areas where the current approaches provide a solid basis for assessments and those areas where improvements are needed or desirable. For those latter areas, options for improvements are being suggested, including, for example, the development of a pan-European food composition database, activities to understand better effects of processing on individual food chemicals, harmonisation of food consumption survey methods with the option of a regular pan-European survey, evaluation of probabilistic models and the development of models to assess exposure to food allergens. In all three areas, the limitations of the approaches currently used lead to uncertainties which can either cause an over- or underestimation of real intakes and thus risks. Given these imprecisions, risk assessors tend to build in additional uncertainty factors to avoid health-relevant underestimates. This is partly done by using screening methods designed to look for "worst case" situations. Such worse case assumptions lead to intake estimates that are higher than reality. These screening methods are used to screen all those chemicals with a safe intake distribution. For chemicals with a potential risk, more information is needed to allow more refined screening or even the most accurate estimation. More information and more refined methods however, require more resources. The ultimate aims are: (1) to obtain appropriate estimations for the presence and quantity of a given chemical in a food and in the diet in general; (2) to assess the consumption patterns for the foods containing these substances, including especially those parts of the population with high consumption and thus potentially high intakes; and (3) to develop and apply tools to predict reliably the likelihood of high end consumption with the presence of high levels of the relevant substances. It has thus been demonstrated that a tiered approach at all three steps can be helpful to optimise the use of the available resources: if relatively crude tools - designed to provide a "worst case" estimate - do not suggest a toxicologically significant exposure (or a relevant deficit of a particular nutrient) it may not be necessary to use more sophisticated tools. These will be needed if initially high intakes are indicated for at least parts of the population. Existing pragmatic approaches are a first crude step to model food chemical intake. It is recommended to extend, refine and validate this approach in the near future. This has to result in a cost-effective exposure assessment system to be used for existing and potential categories of chemicals. This system of knowledge (with information on sensitivities, accuracy, etc.) will guide future data collection.

Animals↗
PubMedDate not supplied

The contribution of epidemiology.

Epidemiologic studies directly contribute data on risk (or benefit) in humans as the investigated species, and in the full food intake range normally encountered by humans. This paper starts with introducing the epidemiologic approach, followed by a discussion of perceived differences between toxicological and epidemiologic risk assessment. Areas of contribution of epidemiology to the risk assessment process are identified, and ideas for tailoring epidemiologic studies to the risk assessment procedures are suggested, dealing with data collection, analyses and reporting of both existing and new epidemiologic studies. The dietary habits and subsequent disease occurrence of over three million people are currently under observation worldwide in cohort studies, offering great potential for use in risk assessment. The use of biomarkers and data on genetic susceptibility are discussed. The paper describes a scheme to classify epidemiologic studies for use in risk assessment, and deals with combining evidence from multiple studies. Using a matrix approach, the potential contribution to each of the steps in the risk assessment process is evaluated for categories of food substances. The contribution to risk assessment of specific food substances depends on the quality of the exposure information. Strengths and weaknesses are summarized. It is concluded that epidemiology can contribute significantly to hazard identification, hazard characterisation and exposure assessment.

Biomarkers↗