Risk characterisation of chemicals in food and diet.
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Consumer Product Safety↗
Biomedical subjects
J Kleiner
Publications and source records attributed to J Kleiner.
Cognitive changes during topiramate therapy.
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Anticonvulsants↗
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↗
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↗
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↗
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↗
Activation energy for surface diffusion of Si on Si(001): A scanning-tunneling-microscopy study.
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Journal Article↗
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↗
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↗
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↗
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↗
Hazard characterisation of chemicals in food and diet. dose response, mechanisms and extrapolation issues.
Hazard characterisation of low molecular weight chemicals in food and diet generally use a no-observed-adverse-effect level (NOAEL) or a benchmark dose as the starting point. For hazards that are considered not to have thresholds for their mode of action, low-dose extrapolation and other modelling approaches may be applied. The default position is that rodents are good models for humans. However, some chemicals cause species-specific toxicity syndromes. Information on quantitative species differences is used to modify the default uncertainty factors applied to extrapolate from experimental animals to humans. A central theme for extrapolation is unravelling the mode of action for the critical effects observed. Food can be considered as an extremely complex and variable chemical mixture. Interactions among low molecular weight chemicals are expected to be rare given that the exposure levels generally are far below their NOAELs. Hazard characterisation of micronutrients must consider that adverse effects may arise from intakes that are too low (deficiency) as well as too high (toxicity). Interactions between different nutrients may complicate such hazard characterisations. The principle of substantial equivalence can be applied to guide the hazard identification and hazard characterisation of macronutrients and whole foods. Macronutrients and whole foods must be evaluated on a case-by-case basis and cannot follow a routine assessment protocol.
Animals↗
Mathematical modelling and quantitative methods.
The present review reports on the mathematical methods and statistical techniques presently available for hazard characterisation. The state of the art of mathematical modelling and quantitative methods used currently for regulatory decision-making in Europe and additional potential methods for risk assessment of chemicals in food and diet are described. Existing practices of JECFA, FDA, EPA, etc., are examined for their similarities and differences. A framework is established for the development of new and improved quantitative methodologies. Areas for refinement, improvement and increase of efficiency of each method are identified in a gap analysis. Based on this critical evaluation, needs for future research are defined. It is concluded from our work that mathematical modelling of the dose-response relationship would improve the risk assessment process. An adequate characterisation of the dose-response relationship by mathematical modelling clearly requires the use of a sufficient number of dose groups to achieve a range of different response levels. This need not necessarily lead to an increase in the total number of animals in the study if an appropriate design is used. Chemical-specific data relating to the mode or mechanism of action and/or the toxicokinetics of the chemical should be used for dose-response characterisation whenever possible. It is concluded that a single method of hazard characterisation would not be suitable for all kinds of risk assessments, and that a range of different approaches is necessary so that the method used is the most appropriate for the data available and for the risk characterisation issue. Future refinements to dose-response characterisation should incorporate more clearly the extent of uncertainty and variability in the resulting output.
Animals↗
Hazard identification by methods of animal-based toxicology.
This paper is one of several prepared under the project "Food Safety In Europe: Risk Assessment of Chemicals in Food and Diet" (FOSIE), a European Commission Concerted Action Programme, organised by the International Life Sciences Institute, Europe (ILSI). The aim of the FOSIE project is to review the current state of the science of risk assessment of chemicals in food and diet, by consideration of the four stages of risk assessment, that is, hazard identification, hazard characterisation, exposure assessment and risk characterisation. The contribution of animal-based methods in toxicology to hazard identification of chemicals in food and diet is discussed. The importance of first applying existing technical and chemical knowledge to the design of safety testing programs for food chemicals is emphasised. There is consideration of the presently available and commonly used toxicity testing approaches and methodologies, including acute and repeated dose toxicity, reproductive and developmental toxicity, neurotoxicity, genotoxicity, carcinogenicity, immunotoxicity and food allergy. They are considered from the perspective of whether they are appropriate for assessing food chemicals and whether they are adequate to detect currently known or anticipated hazards from food. Gaps in knowledge and future research needs are identified; research on these could lead to improvements in the methods of hazard identification for food chemicals. The potential impact of some emerging techniques and toxicological issues on hazard identification for food chemicals, such as new measurement techniques, the use of transgenic animals, assessment of hormone balance and the possibilities for conducting studies in which common human diseases have been modelled, is also considered.
Animals↗
Methods of in vitro toxicology.
In vitro methods are common and widely used for screening and ranking chemicals, and have also been taken into account sporadically for risk assessment purposes in the case of food additives. However, the range of food-associated compounds amenable to in vitro toxicology is considered much broader, comprising not only natural ingredients, including those from food preparation, but also compounds formed endogenously after exposure, permissible/authorised chemicals including additives, residues, supplements, chemicals from processing and packaging and contaminants. A major promise of in vitro systems is to obtain mechanism-derived information that is considered pivotal for adequate risk assessment. This paper critically reviews the entire process of risk assessment by in vitro toxicology, encompassing ongoing and future developments, with major emphasis on cytotoxicity, cellular responses, toxicokinetics, modelling, metabolism, cancer-related endpoints, developmental toxicity, prediction of allergenicity, and finally, development and application of biomarkers. It describes in depth the use of in vitro methods in strategies for characterising and predicting hazards to the human. Major weaknesses and strengths of these assay systems are addressed, together with some key issues concerning major research priorities to improve hazard identification and characterisation of food-associated chemicals.
Animal Testing Alternatives↗