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Objective Examine the characteristics of recent head and neck oncology (H&N) fellowship graduates and assess their current perceptions of career alignment and satisfaction. Methods H&N fellowship graduates from American Head & Neck Society (AHNS)-accredited programs between 2015 to 2020 were surveyed. Two-sample t-tests and analysis of variance tests were used to determine the effect of respondents’ demographics, fellowship characteristics, career preferences, and current practice on their degree of career alignment with expectations and overall job satisfaction. Results Fifty-eight fellowship graduates completed the cross-sectional survey. Fifty-two of all respondents (89.7%) primarily preferred an academic job, of whom 5 (9.6%) went into private practice. Respondents in private practice, those treating general Otolaryngology patients, or those who do not work with residents demonstrated significantly poorer job alignment and career satisfaction compared to those in academic medicine, those only treating H&N patients, or those working with residents, respectively. Discussion The number of desirable academic positions each year may be insufficient for graduating fellows. By setting realistic career expectations, planning for a mixed scope of practice, and integrating resident involvement into private practice groups, H&N providers may ultimately find more fulfillment in their work. These findings could be valuable to fellowship programs in designing training and to future H&N fellows in their career planning. Further studies with higher power would be warranted to identify other indicators of H&N career satisfaction and ways to reduce physician burnout.

Sudden sensorineural hearing loss (SSNHL) is uncommon and oftentimes idiopathic. We describe the unique presentation of SSNHL in an HBO chamber employee following a parotidectomy, whose chief complaint was otalgia and aural fullness during dives. She ultimately recovered completely due to timely diagnosis and a high-dose steroid taper.

Objectives To investigate the potential utility of intra-oral ultrasound (IOUS) in guiding deep margin clearance and measuring depth of invasion (DOI) of oral tongue carcinomas (OTC). Materials and Methods Retrospective chart review of consecutive patients with T1-T3 OTC who underwent intraoperative ultrasound-guided resection and a comparator group that had undergone resection without the use of IOUS both by a single surgeon. Data was extracted from operative, pathology and radiology reports. Deep margins and DOI were reviewed by a dedicated head and neck pathologist. Correlation between histologic and ultrasound DOI was assessed using Pearson correlation. Results A total of 23 patients were included in the study cohort with a comparator group of 21 patients in the control group. None of the patients in the study cohort had a positive (cut-through) deep margin and the mean deep margin clearance was 8.5 ± 4.9 and 6.7 ± 3.8 for the IOUS and non-IOUS groups respectively (p-value 0.18) showing a non-significant improvement in the IOUS group. As a secondary outcome, there was a strong correlation between histologic and ultrasound DOI (0.9449). Conclusion Ultrasound appears to be a potentially effective tool in guiding OTC resections. In this small series, IOUS facilitated deep margin clearance and resulted in a non-statistically significant increase in deep margin clearance. Intraoral ultrasound can accurately measure lesional DOI.

Longer channels within serpentine flow fields are highly effective at removing liquid water slugs and have little water accumulation; however, the long flow path causes a large pressure drop across the cell. This results in both a significant concentration gradient between the inlet and outlet, and high pumping losses. Parallel flow fields have a shorter flow path and smaller pressure drop between the inlet and outlet. This low pressure drop and multiple routes for reactants in parallel channels allows for significant formation of liquid water slugs and water accumulation. To investigate these differences, a polymer electrolyte membrane fuel cell parallel flow field with the ability to modify the length of the channels was designed, fabricated, and tested. Polarization curves and the performance, water accumulation, and pressure drop were measured during 15 min of 0.5 A cm −2 steady-state operation. An analysis of variance was performed to determine if the channel length had a significant effect on performance. It was found that the longer 25 cm channels had significantly higher and more stable performance than the shorter 5 cm channels with an 18% and an 87% higher maximum power density and maximum current density, respectively. Channel lengths which result in a pressure drop, across the flow field, slightly larger than that required to expel liquid water slugs were found to have minimal water accumulation and high performance, while requiring minimal parasitic pumping power.

To better define the molecular basis of multiple myeloma (MM), we performed unsupervised hierarchic clustering of mRNA expression profiles in CD138-enriched plasma cells from 414 newly diagnosed patients who went on to receive high-dose therapy and tandem stem cell transplants. Seven disease subtypes were validated that were strongly influenced by known genetic lesions, such as c-MAF– and MAFB-, CCND1- and CCND3-, and MMSET-activating translocations and hyperdiploidy. Indicative of the deregulation of common pathways by gene orthologs, common gene signatures were observed in cases with c-MAF and MAFB activation and CCND1 and CCND3 activation, the latter consisting of 2 subgroups, one characterized by expression of the early B-cell markers CD20 and PAX5. A low incidence of focal bone disease distinguished one and increased expression of proliferation-associated genes of another novel subgroup. Comprising varying fractions of each of the other 6 subgroups, the proliferation subgroup dominated at relapse, suggesting that this signature is linked to disease progression. Proliferation and MMSET-spike groups were characterized by significant overexpression of genes mapping to chromosome 1q, and both exhibited a poor prognosis relative to the other groups. A subset of cases with a predominating myeloid gene expression signature, excluded from the profiling analyses, had more favorable baseline characteristics and superior prognosis to those lacking this signature.

Ochratoxin A (OTA) causes nephropathy in all species tested with large sex and species differences in potency, pigs being most sensitive. It has been linked to Balkan endemic nephropathy (BEN) in humans. Embryotoxicity, teratogenicity, and immunotoxicity occur only at doses higher than those causing nephrotoxicity. OTA has long serum half-lives in various species including humans. OTA produced renal tumours in mice and rats. The male rat was most sensitive, renal carcinomas occurring after 70 microg/kg bw per day but not 21 microg/kg bw per day. OTA was not mutagenic in most studies in bacteria and mammalian cells, but produced DNA damage and chromosomal aberrations in mammalian cells in vitro, and in mice in vivo. DNA adducts found in the kidneys of mice and rats dosed with OTA, did not contain fragments of OTA. OTA in food has been evaluated by the Joint FAO/WHO Expert Committee on Food Additives (JECFA), and by the EC Scientific Committee on Food (SCF). JECFA established a provisional tolerable weekly intake (PTWI) of 100 ng/kg bw based on the LOEL for renal effects in pigs. Conversely, SCF recommended reducing exposure to OTA as much as possible, e.g. below 5 ng/kg bw per day. Both committees recommended further studies to clarify the mechanism by which OTA induces nephrotoxicity and carcinogenicity.

Although botanicals have played a role in the marketing of health products for ages, there is an increased interest today due to their perceived health benefits. Not only do consumers increasingly take charge of their health, but the scientific information and understanding of the beneficial health effects of bioactive substances in food, functional foods and food supplements have improved. Increasing use of these products has also led to concerns about their actual safety. Recorded cases of intoxications have triggered such concerns. The safety assessment of these substances is complicated by, amongst others, the variability of composition. Furthermore, consumption of such functional products is expected to produce physiological effects, which may lead to low margins of safety as the margin between exposure of such products and the safe level of intake are likely to be small. The safety assessment of botanicals and botanical preparations in food and food supplement should at least involve: the characterisation and quality of the material, its quality control; the intended use and consequent exposure; history of use and exposure; product comparison(s); toxicological information gathering; Risk characterisation/safety assessment. As a guidance tool, a decision tree approach is proposed to assist in determining the extent of data requirements based on the nature of the such product. This guidance tool in safety assessment was developed by an expert group of the International Life Sciences Institute (ILSI), European Branch, and is currently in press. In this paper a summarised version of this tool is presented.

The increasing use of botanical food supplements has raised concerns among scientific and regulatory communities. Occasional cases of intoxication have occurred from misuse, misidentification of the botanical species or contamination with extraneous plants. Consequently, risk assessment of botanical products requires adequate specification of identity and composition. Sources vary from staple food plants to herbals used in folk medicine; the supplement may comprise the whole plant, extracts thereof or purified components. This variability poses problems in adopting a generic approach to their risk assessment. The nature and extent of toxicological testing required will depend on: nature of the supplement, prior knowledge of human consumption, likely exposure and nutritional impact, and intended beneficial effects. Generally, for herbs or complex extracts, it is not possible to make a risk assessment on the basis of a single active component as more than one may be of toxicological significance and matrix effects may affect bioavailability. Nevertheless, studies on single components may be useful in elucidating potential interactions. Botanical supplements are intended to produce physiological effects, so there is a need to distinguish a No Observed Effect Level from a No Observed 'Adverse' Effect Level and the margin of exposure between that producing the desired effect and the upper safe level may be smaller than that adopted for food additives and contaminants. Human studies of efficacy and possible side effects may help in determining the acceptable margin of exposure. A decision tree will be presented to assist in determining the extent of data requirements based on the nature of the product.

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.

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.

The de,minimis concept acknowledges a human exposure threshold value for chemicals below which there is no significant risk to human health. It is the underlying principle for the US Food and Drug Administration (FDA) regulation on substances used in food-contact articles. Further to this, the principle of Threshold of Toxicological Concern (TTC) has been developed and is now used by the joint FAO/WHO Expert Committee on Food Additives (JECFA) in their evaluations. Establishing an accepted TTC would benefit consumers, industry and regulators, since it would preclude extensive toxicity evaluations when Lumen intakes are below such threshold, and direct considerable time and cost resources towards testing substances with the highest potential risk to human health. It was questioned, however, whether specific endpoints that may potentially give rise to low-dose effects would be covered by such threshold. In this review., the possibility of defining a TTC for chemical substances present in the diet was examined for general toxicity endpoints (including carcinogenicity), as well as for specific endpoints, namely neurotoxicity and developmental neurotoxicity, immunotoxicity and developmental toxicity. For each of these endpoints, a database of specific no-observed-effect levels (NOELs) was compiled by screening oral toxicity studies. The substances recorded in each specific database were selected on the basis of their demonstrated adverse effects. For the neurotoxicity and developmental neurotoxicity databases, it was intended to cover all classes of compounds reported to hare tither a demonstrated neurotoxic or developmentally neurotoxic effect, or at least, on a biochemical or pharmacological basis were considered to have a potential for displaying such effects. For the immunotoxicity endpoint, it was ensured that only immunotoxicants were included in the database by selecting most of the substances from the Luster er al. database, provided that they satisfied the criteria for immunotoxicity defined by Luster. For the developmental toxicity database, substances were selected from the Munro ct nl. database that contained the lowest NOELs retrieved from the literature for more than 600 compounds. After screening these, substances shelving any effect which could point to developmental toxicity as broadly defined by the US EPA (1986) were recorded in the database. Additionally., endocrine toxicity and allergenicity, were addressed as two separate cases, using different approaches and methodology. The distributions of NOELs for the neurotoxicity, developmental neurotoxicity and developmental toxicity endpoints were compared with the distribution of NOELs for non-specific carcinogenic endpoints. As the immunotoxicity database was too limited to draw such a distribution of immune NOELs, the immunotoxicity endpoint,vas evaluated by comparing immune NOELs (or LOELs-lowest-observed-effect levels-when NOELs were not available),vith non-immune NOELs (or LOELs), in order to compare the sensitivity of this endpoint with non-specific endpoints. A different methodology was adopted for the evaluation of the endocrine toxicity endpoint since data currently available do not permit the establishment of a clear causal link between endocrine active chemicals and adverse effects in humans. Therefore, this endpoint was analysed by estimating the human exposure to oestrogenic environmental chemicals and evaluating their potential impact on human health, based on their contribution to the overall exposure, and their estrogenic potency relative to endogenous hormones. The allergenicity endpoint was not analysed as such. It was addressed in a separate section because this issue is not relevant to the overall population but rather to subsets of susceptible individuals, and allergic risks are usually controlled by other means (i.e, labelling) than the Threshold of Toxicological Concern approach. However, as several researchers are currently examining the existence of a threshold in allergy, the possibility of determining threshold doses for food allergens was put into perspective, and the likelihood for chemical substances to induce allergy at dietary relevant doses was discussed. The analysis indicated that, within the limitation of the databases, developmental neurotoxicity and developmental toxicity were not more sensitive than other non-specific endpoints. Although the cumulative distribution of NOELs for neurotoxic compounds was significantly loner than those for other non-cancer endpoints, these substances were accommodated within the TTC of 1.5 mu g/person/day. Furthermore, the analysis demonstrated that none of the specific non-cancer endpoints evaluated in the present study was more sensitive than cancer and, that a TTC of 1.5 mu g/person/day based on cancer endpoints provides an adequate margin of safety. Analysis of the immunotoxicity database should that for the group of immunotoxicants examined here, the specific immunotoxic endpoint was not more sensitive than other endpoints. In other words, the distribution of immunotoxic NOELs for these compounds did not appear to differ from the distribution of nonspecific endpoints NOELs for the same compounds. The dietary intakes of environmental oestrogenic chemicals were estimated and their oestrogenic potencies were compared with that of endogenous hormones, in order to assess their impact on human health. The results are in line with scientific data obtained so far, suggesting that estrogenic compounds of anthropogenic origin, in comparison with endogenous hormones, possess only little hormonal activity lilts phytoestrogens. Results of animal studies do not suggest that hormonal effects are to be expected from the rather lon concentrations found in foods. More data are necessary to determine threshold doses for food allergens. However, provided that numerous criteria need to be satisfied before sensitization occurs, it is unlikely that small molecules used in little amounts in foods would induce such reactions. On the basis of the present analysis, which was conducted using conservative assumptions at each step of the procedure (i.e. in data compilation and data analysis), and continually adopting a "worst case" perspective, it can be concluded that a Threshold of Toxicological Concern of 1.5 mu g/person/day provides adequate safety assurance. Chemical substances present in the diet that are consumed at levels below this threshold pose no appreciable risk. Moreover, for compounds which do not possess structural alerts for genotoxicity and carcinogenicity, further analysis mag indicate that a higher Threshold of Toxicological Concern mag he appropriate. (C) 2000 Elsevier in Science Ltd. All rights reserved.

The acceptable daily intake (ADI) for food additives is commonly derived from the NOAEL (no-observed-adverse-effect level) in long-term animal in vivo studies. To derive an ADI a safety or uncertainty factor (commonly 100) is applied to the NOAEL in the most sensitive test species. The 100-fold safety factor is considered to be the product of both species and inter-individual differences in toxicokinetics and toxicodynamics. Although in vitro data have previously been considered during the risk assessment of food additives, they have generally had no direct influence on the calculation of ADI values. In this review 18 food additives are evaluated for the availability of in vitro toxicity data which might be used for the derivation of a specific data-derived uncertainty factor. For the majority of the food additives reviewed, additional in vitro tests have been conducted which supplement and support the short- and long-term in vivo toxicity studies. However, it was recognized that these in vitro studies could not be used in isolation to derive an ADI; only when sufficient in vivo mechanistic data are available can such information be used in a regulatory context. Additional short-term studies are proposed for the food additives which, if conducted, would provide data that could then be used for the calculation of data-derived uncertainty factors. Copyright (C) 2000 Elsevier Science B.V.

The significance of excursions of intake above the ADI, TDI, or PTWI can only be assessed by reference to the database which led to the derivation of these, most particularly the duration of the pivotal study (chronic, subchronic, acute), the pharmacokinetic parameters, and the nature of toxicity and mechanism of action. Although this implies a case by case assessment, a number of typical situations may be recognized: (1) The substance (usually a contaminant, not an additive) has a very long half-life leading to accumulation in target organs/tissues, e.g., Cd or dioxin. The chronic toxicity is manifested when critical concentrations are achieved in these tissues and there is a large difference between the acutely toxic dose and the chronic NOAEL. In such a case, the effect of excursions above the PTWI on tissue levels is readily calculated; peak excursions of several times the PTWI for short periods (days, weeks, or even months) or lower peak intakes for even longer periods (months to years) may be inconsequential provided that the integrated exposure over longer periods does not lead to critical steady-state tissue concentrations being achieved. (In such cases, it is clearly inappropriate to divide the PTWI by 7 and treat this as an ADI.) (2) A more common situation for food additives is where the ADI is based on a chronic study, but the t 1/2 is short, i.e., the situation is one of chronic stress rather than cumulative toxicity. In such cases, e.g., BHA or BHT, the effects on the target organ (hyperplasia, foci of altered cells, etc.) can usually be identified in subchronic studies, although progressive changes may occur in chronic studies. Two subsituations then arise. First, when the effects seen at the LOAEL in subacute/subchronic studies are truly reversible (e.g., methemoglobinemia), short-term studies with a reversibility component may become pivotal in assessing the consequences of short-term excursions above the ADI. Second, when the short-term effects are not fully reversible, or are even progressive, the consequences of short-term peaks of intake above the ADI would require careful evaluation against the NOAEL or LOAEL in subacute or subchronic studies. (3) A rare situation might arise where the ADI is based on a chronic toxicity study but the margins between the chronic NOAEL and some aspects of acute toxicity may be small. For example, for a compound which behaved like retinol, the ADI might be based on chronic effects on the liver but at maternally nontoxic doses the substance may be teratogenic following acute exposure during early pregnancy. Clearly in such a situation, the acute NOAEL for teratogenicity would be used appropriately to evaluate the risks associated with short-term peaks of exposure, i.e., a different study may be pivotal in determining the effects of large excursions above the ADI than that which was used to calculate it. Clearly, these cases are not comprehensive but do provide a framework against which to discuss the potential effects of excursions above the ADI and to reach rational conclusions which are not based on the misapprehension that the ADI (or worse, the PTWI × 7) is a lower bound of toxicity.

Aqueous extracts of green tea, at concentrations of 2.5. 5.0 and 7.5%, were administered to rats as the sole drinking fluid for 4 weeks. Hepatic glutathione S-transferase (GST) activity, determined using 1-chloro-2,4-dinitrobenzene (CDNB) and 3,4-dichloronitrobenzene (DCNB) as substrates, and UDP-glucuronosyl transferase activity, determined using 2-aminophenol as substrate, were induced but the effect was not always dose dependent. At the two highest doses, hepatic catalase activity was inhibited. In a second study, animals were exposed for 4 weeks to aqueous extracts (2.5%, v/v) of green tea, black tea (which has a much lower content of flavanols compared with green tea) and decaffeinated black tea. Treatment with the black tea enhanced GST activity, whether monitored using CDNB or DCNB, and the glucuronidation of 2-aminophenol. Treatment with decaffeinated black tea failed to modulate any of these activities, whereas treatment with green tea only enhanced the glucuronidation of 2-aminophenol. Finally, at this concentration of tea extract administration, black and decaffeinated black tea, but not green tea, suppressed catalase activity. It is concluded that neither flavanols nor caffeine are responsible for the induction of hepatic Phase II activities and inhibition of catalase activity in the rat.

The present study was undertaken to evaluate the role of individual flavanols in the antimutagenic potential of green tea. Aqueous extracts of green tea were fractionated into four fractions, each of which was fully defined with respect to its content of (-)-epigallocatechin gallate, (-)-epicatechin gallate, (-)-epigallocatechin, (-)-epicatechin and gallic acid. The ability of each fraction to antagonize the mutagenicity of four model mutagens, namely N-nitrosopyrrolidine, benzo(a)pyrene, 2-aminoanthracene and Glu-P-1 (2-amino-6-methyldipyrido[1,2-a: 3,2-d]imidazole), was investigated in the Ames test. No correlation could be established between any of the flavanols and antimutagenic potential. Similarly, no correlation was evident between the flavanol content of each fraction and its ability to inhibit CYP1A, as exemplified by the O-dealkylations of methoxy- and ethoxy-resorufin. Furthermore, no relationship could be established between CYP2B activity, as exemplified by the O-depentylation of pentoxyresorufin and the antimutagenic potential of green tea. Using a modified Ames test procedure, the ability of each tea fraction to scavenge the metabolically generated reactive intermediates of the model mutagens was investigated, this being an additional mechanism of the antimutagenic potential of green tea. Generally, fractions with high flavanol content were more effective scavengers. It is concluded that the contribution of flavanols to the antimutagenic activity of green tea is, at best, limited. ©1997 SCI

Agaritine (N 2 -[ L -(+)-glutamyl]-4-(hydroxymethylphenyl)hydrazine), the principal hydrazine found in the edible mushroom Agaricus bisporus , as well as the N ′-acetyl derivative of 4-(hydroxymethyl)phenylhydrazine and 4-(hydroxymethyl)benzene diazonium ion, as the tetraborate salt, considered as the putative proximate and ultimate carcinogens of agaritine, were all synthesised chemically. The mutagenicity of these compounds and of 4-hydrazinobenzoic acid, a precursor of agaritine biosynthesis in mushroom, was investigated in the Ames test, using Salmonella typhimurium strain TA104, in the absence and in the presence of either mushroom tyrosinase or rat hepatic cytosol as activation systems. In the absence of an activation system the diazonium ion was clearly the most mutagenic of the four compounds studied. When tyrosinase was used as activation system, the mutagenicity of N ′-acetyl-4-(hydroxymethyl)phenylhydrazine was enhanced; glutathione and superoxide dismutase markedly suppressed the mutagenic response. When the mutagenicity of the four compounds was evaluated in the presence of rat hepatic cytosol, an increase was seen only in the case of N ′-acetyl-4-(hydroxymethyl)phenylhydrazine; this was shown to be due to deacetylation releasing the more mutagenic free hydrazine. Collectively, the above data are compatible with an activation of agaritine that involves an initial loss of the γ -glutamyl group followed by microsomal oxidation of the free hydrazine to generate the diazonium ion. Also of interest is the observation that mushroom tyrosinase can convert N ′-acetyl-4-(hydroxymethyl)phenylhydrazine to mutagenic product(s); whether these products contribute to the mutagenicity of mushroom extracts remains to be established.

The diversity of novel foods and novel ingredients covered by the scope of the EU regulation is such that a check list approach to safety evaluation is inappropriate. Rather, a case-by-case approach is required taking into account the composition of the novel food, its intake, its role in the diet and the intended target group. The SAFEST approach provides a means of targeting the safety evaluation on those aspects, nutritional or toxicological, of a novel food which are of particular concern. Using this approach, novel foods are assigned to one of three classes on the basis of certain background information. For those novel foods which can be shown to be in SAFEST class 1, namely those which are substantially equivalent to a traditional counterpart, no further information is required to demonstrate their safety. For those novel foods in SAFEST class 2, i.e. those sufficiently similar to a traditional counterpart or differing from it only in particular, well defined, characteristics, the evaluation will focus on those differences. Only in the case of novel foods which are not in class 1 or class 2 is extensive testing of the whole food likely to be required. Even in these cases, the testing should follow a scientifically-based hierarchical approach involving: literature reviews; chemical analysis; appropriate in vitro and in vivo tests; and, if necessary, confirmation of safety and nutritional value in humans. Examination of the causes of any adverse effects reported by consumers after the novel food or ingredient has been approved and is introduced into the market may provide additional reassurance of safety.

Nitrites and nitrates occur as dietary constituents being particularly high in certain vegetables. Endogenous oxidation of nitric acid also produces nitrate. Nitrate is readily absorbed and rapidly excreted in urine (60-70%) with an elimination half life of about five hours. Nitrate is secreted by an active transport mechanism (25%) into saliva; and by passive diffusion into breast milk. About 3% nitrate appears in urine as urea and ammonia in humans; in rats this is about 11%. Nitrate is reduced to nitrite by both mammalian enzymes and nitrate reductases present in microorganisms residing in the gastrointestinal tract. In rats approximately 50% of the nitrate reduced to nitrite is produced by mammalian enzymes, the remainder by microorganisms; this ratio is species dependent. Nitrite is absorbed by the gastrointestinal tract and is rapidly oxidised to nitrate. The plasma half life is less than an hour in most species and consequently nitrite is not normally detected in body tissues and fluids after oral administration. Nitrite is oxidised via a coupled reaction with oxyhaemoglobin producing methaemoglobin (ferrihaemoglobin). It appears in certain cases that endogenous nitrite may be a major factor in this process rather than exogenous material. Nitrite or a chemical species derived from it may be involved in the generation of nitrosamines and nitrosamides of toxicological importance, although neither nitrite or nitrate are carcinogenic.

The mutagenicity of commercially available white grape juice was evaluated in the Ames mutagenicity test. Grape juice elicited a positive mutagenic, response in Salmonella typhimurium strain TA104 and a weaker response in strains TA97, TA98, TA100 and TA1530. The mutagenic response was evident in the absence of an activation system and inclusion of such a system did not influence mutagenicity. The grape juice-mediated mutagenic response was not due to histidine residues in the juice or likely treatment with sulfite. Moreover, freshly prepared grape juice displayed a similar mutagenic response. Three different brands of commercially available white grape juice were investigated in the Ames test; they all provoked a clear positive mutagenic response, but the degree of mutagenicity differed and could not be attributed to differences in the content of solids. It is concluded that grapes contain direct-acting genotoxic component(s).

A group of 19 acyclic terpenes have been evaluated for potential toxicity/carcinogenicity by molecular orbital determinations of their spatial and electronic parameters, and hence prediction of their metabolic activation or detoxication by the cytochrome P-450 (CYP) superfamily of mixed-function oxidase enzymes. Previous studies have characterized the spatial dimensions of the CYP1A1, 1A2 and 2E1 enzymes, which are known to activate mutagens and carcinogens and to be involved in other mechanisms of toxicity. None of the terpenes was found to have shape or electronic parameters appropriate for metabolic activation by CYP1A1 or 1A2, and hence they are unlikely to be carcinogenic or mutagenic. Furthermore, none of these chemicals had spatial parameters critical for substrates of CYP2E, and they are therefore unlikely to induce the formation of reactive oxygen species (ROS) or to initiate or promote malignancy or toxicity by mechanisms involving ROS. However, citral, and others of these terpenes, are known to undergo metabolism to carboxylic acids that may induce CYP4, and are therefore possible inducers of hepatic peroxisomal proliferation at high dosage, which may have implications for possible hepatotoxicity.

The present study was undertaken in order to evaluate the in vitro and ex vivo antimutagenicity of anthracene against the food-borne carcinogen IQ (2-amino-3-methylimidazo[4,5- f ]quinoline). Anthracene caused a marked, concentration-dependent decrease in the mutagenicity of IQ in the Ames test, whether hepatic S9 or isolated microsomes from Aroclor 1254-induced rats served as the activation systems. Anthracene gave rise to a concentration-dependent inhibition of the 0-deethylation of ethoxyresorufin, a diagnostic probe for CYP1A (cytochrome P450 family 1, subfamily A) activity, and of the metabolic activation of Glu-P-1 (2-amino-6-methyldipyrido[1,2- a :3′,2′- d ]midazole, a diagnostic probe for CYP1A2. When microsomal metabolism of IQ was terminated by menadione, incorporation of anthracene into the incubation mixture once again inhibited the mutagenicity of IQ. All the above observations indicate that anthracene owes its antimutagenic response against IQ to: (a) inhibition of its CYP1A-mediated activation and (b) direct interaction between anthracene and the reactive intermeidiate(s) of IQ leading to mediated activation and (b) direct interaction between anthracene and the reactive intermediate(s) of IQ leading to their inactivation. Treatment of rats with anthracene did not greatly infuence the ability of hepatic preparations to bioactivate IQ to mutagens. Similarly, administration of anthracene 2 h before sacrifice to Aroclor 1254-pretreated rats, did not modulate the hepatic activation of IQ. These findings demonstrate that th ein vitro mechanisms of the antimutagenicity of anthracene are not operative in vivo, and further illustrate the inadequacy of in vitro studies, conducted in isolation, in predicting such effects.

In the present study aqueous extracts of green tea, at the concentrations customarily consumed by humans, were evaluated for their antimutagenic activity against major classes of dietary and occupational carcinogens. Green tea extracts caused a very marked and concentration-dependent inhibition of the Aroclor 1254-hepatic S9-mediated mutagenicity of heterocyclic amines (IQ and Glu-P-1) and polycyclic aromatic hydrocarbons (benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene) and of the isoniazid-induced S9-mediated mutagenicity of nitrosamines (nitrosopiperidine and nitrosopyrrolidine). Similar inhibition was seen in the mutagenicity of the two aromatic amines, namely 2-amino-fluorene and 2-aminoanthracene, whether Aroclor 1254-S9, isolated microsomes or cytosol served as the activation system. Finally, the mutagenicity of the direct-acting mutagens 9-aminoacridine and MNNG was also suppressed by green tea extracts, but the effect was less pronounced when compared with the indirect-acting mutagens. Green tea extracts caused a marked and concentration-dependent decrease in the O-dealkylation of methoxyresorufin, ethoxyresorufin and pentoxyresorufin. A similar inhibition of the NADPH-dependent reduction of cytochrome c was also observed. Following the termination of the microsomal metabolism of the various promutagens, incorporation of green tea extracts into the activation system resulted in a comparatively modest inhibition of their mutagenic response. It is concluded that aqueous extracts of green tea possess marked antimutagenic potential against a variety of important dietary and environmental mutagens. Two mechanisms appear to be responsible. The first involves a direct interaction between the reactive genotoxic species of the various promutagens and nucleophilic tea component(s) present in the aqueous extracts.(ABSTRACT TRUNCATED AT 250 WORDS)

Both epidemiological and experimental evidence indicate that environmental factors may modulate chemical toxicity. Of these, dietary factors have been most thoroughly studied and shown to modulate a number of toxic processes including carcinogenesis. Total energy intake and specific nutrients (protein and specific amino acids, vitamins, and minerals) have been shown to be active in this regard as have a number of non-nutritive dietary factors, most notably phenolic and sulphur-containing compounds, and indoles. The mechanisms by which dietary factors might influence toxicity include effects on bioavailability, phase I or phase II metabolism, scavenging of reactive metabolites, induction of DNA repair processes, inhibition of cell proliferation, induction of differentiation or apoptosis and effects on the immune system. These factors are discussed with emphasis on dietary exposure to modulating factors.

eCall is an eSafety technology giving automatic notification of vehicles involved in “a crash situation” to the emergency services, whilst the vehicle is in a mobile phone coverage area. The principal benefits of eCall are reported to be safety-related; alerting emergency services to the exact location of an incident allows quicker and more effective medical assistance. However, recent work for the Highways Agency [1] and for the European Commission [6] have, for the first time, identified and quantified the potential benefits in utilising eCall data for traffic management and congestion reduction. This paper briefly reviews the European situation with eCall and describes some of the potential implications for the HA if eCall were implemented in the UK.

Evidence is presented which establishes that mackerel fed in captivity can, by relay from contaminated shellfish via sand eels, accumulate paralytic shellfish poisons (PSP) in the edible flesh at a level (250 micrograms saxitoxin equivalents per kg) similar to that in the contaminated shellfish. Data from ELISAs performed independently in two laboratories show that commercial mackerel fillets which have been associated with incidents of scombrotoxicosis contained 0.02-1.30 micrograms saxitoxin equivalents per kg, concentrations some two to four orders of magnitude below that normally detectable by the mouse bioassay. The doses, expressed as saxitoxin equivalents, administered inadvertently during volunteer testing of such fillets ranged up to 0.5 ng/kg bw, at least four orders of magnitude less than the fatal oral dose for an adult. The doses associated with the rapid induction of nausea/vomiting and/or diarrhoea, 0.11-1.0 ng/kg bw, could not be distinguished from the doses which failed to produce such symptoms in susceptible volunteers (up to 0.5 ng/kg bw). Factors that might explain this lack of correlation between dose (saxitoxin equivalents) and volunteer response are discussed along with previously published reports of PSP relay through the food web. It is suggested that the relay of algal toxins, particularly PSP, but possibly in combination with diarrheic shellfish poisons, may be responsible for scombrotoxicosis.

Hembras de la garrapata Rhipicephalus appendiculatus fueron alimentadas artificial­mente con medio de cultivo celular contenido en tubos capilares, con el objeto de inducir la secreción natural de saliva en el medio. Estas secreciones salivares son una fuente impor­tante de material antigénico para estudios so­bre la resistencia del huésped a la garrapata. Como medio se utilizó una solución balancea­da de sales ''Hank", y en él se evaluó el efecto de la adición de tres concentraciones diferen­tes de albumina sérica bovina sobre la acepta­ción de las garrapatas para alimentarse en el medio. También se avaluó el efecto producido por la adición del fagoestimulante "glutatión reducido" en cada concentración de proteína. En el primer grupo de experimentos, garrapa­tas previamente alimentadas sobre conejos durante cuatro días, demostraron mayores aumentos de peso (P

The ability of the plant phenol ellagic acid to inhibit the mutagenicity of the food mutagen IQ was evaluated using Salmonella typhimurium strain TA98 in the Ames mutagenicity test. Ellagic acid caused a concentration-dependent decrease in the S-9- and microsome-mediated mutagenicity of IQ. The plant phenol did not interact directly with the IQ-derived mutagenic species and did not modify the cytosol-mediated activation of the promutagen. At the concentrations used in the mutagenicity studies, ellagic acid failed to inhibit microsomal mixed-function oxidase activity, including that mediated by the P450I family responsible for the bioactivation of IQ, despite being an essentially planar molecule as indicated by computer-graphic analysis. The inhibitory effect of ellagic acid was independent of its ability to chelate Mg2+. However, pre-incubation of ellagic acid with the bacteria, followed by removal of the plant phenol, did not completely prevent the inhibitory effect of the phenol on the mutagenicity of IQ. Intraperitoneal administration of ellagic acid to rats caused a decrease in total cytochrome P-450 levels and related activities as well as in cytosolic glutathione S-transferase activity. Finally, the possibility that the reported anticarcinogenic action of ellagic acid reflects nothing more than non-selective destruction of hepatic cytochromes P-450, and thus reduced chemical activation, is considered.

Risk assessment of micronutrients has to take into account two different intake-response relationships; the risk of deficiency, which decreases with increase in intake, and the risk of toxicity, which increases with increase in intake. The available databases on micronutrients tend to focus on benefits at low intakes, and there are usually few reliable data on hazard identification and characterisation at high intakes. Application of the usual default uncertainty factors for species differences, human variability and database inadequacy could result in "recommended" upper intake levels that would cause deficiency. There have been a number of comprehensive reviews that have used low, and largely arbitrary, uncertainty factors to establish tolerable upper intake levels for vitamins and minerals. A recent FAO/WHO Workshop developed a structured approach to the application of a single composite uncertainty factor. Risk-benefit approaches have been developed recently that balance the risk of toxicity against the risk of deficiency, and offer the potential for more scientifically based methods.

The hypothesis has been put forward that genotoxic aromatic amines which induce the P450 I family of haemoproteins, the major enzyme involved in their bioactivation, are more likely to be carcinogenic when compared to those chemicals that fail to do so. Induction of the hepatic P450 I family of proteins by carcinogenic aromatic amines and their non-carcinogenic isomers and analogues was investigated in the rat and correlated to their carcinogenic potential. The activity of the P450 I A1 protein was monitored by the O-deethylation of ethoxyresorufin and of the P450 I A2 by the activation of the premutagen Glu-P-1 to mutagenic intermediates in the Ames test. Results were always confirmed immunologically in Western blots employing antibodies to rat P450 I A1 which recognize both proteins of the P450 I family. With all groups of chemicals used in the present study, the members displaying carcinogenicity were always the more potent inducers, while the non-carcinogenic isomers or analogues displayed little or no induction. It appears that a relationship exists between the carcinogenicity of aromatic amines and their ability to induce hepatic P450 I activity.

The hypothesis has been put forward that mutagenic polycyclic aromatic hydrocarbons which induce the P-450 I family of cytochromes, the major enzyme system responsible for their activation, are likely to be carcinogenic. In order to test this hypothesis, rats have been pretreated with a number of polycyclic aromatic hydrocarbons of different mutagenic and carcinogenic potency and hepatic P-450 I activity was monitored using chemical probes such as the O-deethylation of ethoxyresorufin and metabolic activation of Glu-P-1 to mutagens, and immunologically employing polyclonal antibodies against purified rat P-450 I A1. All compounds studied enhanced P-450 I activity and induced P-450 I apoproteins but the extent of induction was very markedly different. The results are discussed with reference to the mutagenicity of these chemicals in the Ames test and their carcinogenicity in the classical mouse skin model. A relationship appears to exist between carcinogenicity of polycyclic aromatic hydrocarbons and their ability to induce hepatic P-450 I activity.

Osteolytic bone disease is the most debilitating manifestation of myeloma. However, myeloma-induced effects on the bone-active cells in the bone marrow are more than just a manifestation of disease--the myeloma derives essential support from the changed balance between bone-forming and -resorbing cells. This observation has lead to the notion that effective control of myeloma bone disease by reducing osteoclast activity and restoring osteoblast activity will contribute to long-term control of myeloma progression. Unlike osteolysis associated with other tumors that metastasize to bone, myeloma-associated lytic lesions are unique in that they do not repair even after many years in complete remission, reflecting a total loss of osteoblastic activity in areas of myeloma foci, apparently induced by the myeloma. Advances in imaging technology including positron emission tomography-computed tomography scanning allows accurate detection of lytic lesions and the monitoring of treatment effects. Effective antimyeloma therapy combined with anti-osteoclast drugs can halt the progression of osteolysis; in severe cases with vertebral compression fractures, effective physical support in the form of vertebroplasty or kyphoplasty is required for control of function, pain, and stature. Fractures of the long bones are usually treated by intramedullary rod placement. New approaches to enhance osteoblast activity while controlling osteoclast activity currently under investigation may prove effective in controlling lytic bone disease and myeloma progression.

Multiple myeloma (MM) growth in the bone marrow is associated with increased osteoclast activity and a reduced number of osteoblasts. Experimental studies suggest that bone disease drives the progression of MM. Whereas those studies focused on the critical role of myeloma-induced osteoclastogenesis in disease progression, little is known about the impact of osteoblasts and increased bone formation on MM.We investigated the effect of isolated osteoblasts and osteoclasts on survival and proliferation of primary MM plasma cells (PC) in co-cultures and triple-cultures, and tested the effect of mesenchymal stem cells (MSC) on bone mineral density and MM growth in myelomatous human bones of SCID-hu mice.Whereas osteoclasts promoted survival and proliferation of MM PC, osteoblasts supported or inhibited MM PC, depending on the source of the MM cells. In triple-cultures osteoblasts attenuated the effect of osteoclasts on MM PC in 18 of 24 experiments. The anti-MM response to osteoblasts correlated with advanced clinical stage. Injection of MSC into myelomatous bones resulted in marked inhibition of tumor growth in three of nine experiments and stabilization of disease in two additional experiments. The anti-MM response of MSC was associated with increased human bone mineral density. Immunohistochemical analysis indicated that the MSC were well engrafted and, in responding mice, differentiated into osteogenic cells.MM PC from the majority of patients are susceptible to growth inhibition by osteoblasts; however, growth of MM PC from certain patients is accelerated by osteoblasts. In vivo, increased bone formation is associated with reduced myeloma burden.

An adverse environment restricted to the time of conception and implantation has been shown to influence later fetal growth and development to term in humans and sheep. In one rat study, protein undernutrition during the pre-implantation period only elevated the systolic blood pressure of the resulting adult offspring. No study has yet followed up adult cardiovascular function in a slower growing, non-litter bearing species after exposure to peri-implantation undernutrition. In the present study, eight ewes were fed to 50% equivalent food intake of twelve control ewes from 1-30 days (term ∼147 days) only. Following consumption of an adequate diet to term, natural lambing and then weaning, basal cardiovascular status and baroreflex function were examined in the resultant young adult offspring. We show that peri-implantation undernutrition has no effect on birth weight or postnatal growth rate but reduces brain weight in the offspring at one year of age i.e. as young adults. Early nutrient restricted sheep also show increased pulse pressure, a reduced rate pressure product and a leftward shift in their baroreflex function curve. However, baroreflex sensitivity in early nutrient restricted sheep is significant blunted during angiotensin II infusion, although not after phenylephrine and sodium nitroprusside treatment. In addition, peri-implantation undernutrition appears to potentiate the tachycardia produced after an experimentally controlled reduction in central blood pressure, relative to controls. The data suggest that peri-implantation undernutrition may program long-term cardiovascular dysfunction that ultimately increases the risk of hypertension in later life. An increase in regional angiotensin II activity during this critical early phase of development is a likely candidate mechanism for the effects observed. The data have broad implications for the health outcome of those offspring from mothers who were poorly nourished during early, often unknown pregnancy and for embryos artificially manipulated because of infertility treatment.

This report presents a review of risk characterisation, the final step in risk assessment of exposures to food chemicals. The report is the second publication of the project Food Safety in Europe: Risk Assessment of Chemicals in the Food and Diet (FOSIE). The science underpinning the hazard identification, hazard characterisation and exposure assessment steps has been published in a previous report (Food Safety in Europe, 2002). Risk characterisation is the stage of risk assessment that integrates information from exposure assessment and hazard characterisation into advice suitable for use in decision-making. The focus of this review is primarily on risk characterisation of low molecular weight chemicals, but consideration is also given to micronutrients and nutritional supplements, macronutrients and whole foods. Problem formulation, as discussed here, is a preliminary step in risk assessment that considers whether an assessment is needed, who should be involved in the process and the further risk management, and how the information will provide the necessary support for risk management. In this step an evaluation is made of whether data are available and what level of resources are needed, as well as the timeline for completing the assessment. The report describes good evaluation practice as an organisational process and the necessary condition under which risk assessment of chemicals should be planned, performed, scrutinised and reported. The outcome of risk characterisation may be quantitative estimates of risks, if any, associated with different levels of exposure, or advice on particular levels of exposure that would be without appreciable risk to health, e.g. a guidance value such as an acceptable daily intake (ADI). It should be recognised that risk characterisation often is an iterative and evolving process. Historically, different approaches have been adopted for the risk characterisation of threshold and non-threshold effects. The hazard characterisation for threshold effects involves the derivation of a level of exposure at or below which there would be no appreciable risk to health if the chemical were to be consumed daily throughout life. A guidance value such as the ADI, is derived from the no-observed-adverse-effect-level (NOAEL) or other starting point, such as the benchmark dose (BMD), by the use of an uncertainty or adjustment factor. In contrast, for non-threshold effects a quantitative hazard estimate can be calculated by extrapolation, usually in a linear fashion, from an observed incidence within the experimental dose-response range to a given low incidence at a low dose. This traditional approach is based on the assumption that there may not be a threshold dose for effects involving genotoxicity. Alternatively, for compounds that are genotoxic, advice may be given that the exposure should be reduced to as low as reasonably achievable (ALARA) or practicable (ALARP). When a NOAEL can be derived from a study in humans, this would be utilised in the derivation of guidance values or advice. However, there may be uncertainties related to the possible role of confounders and the precision of both the incidence and exposure data. Individuals may be at an increased risk because of their greater exposure or their greater sensitivity. Risk characterisation should include information not only on the general population, but also on any subpopulation considered to be potentially susceptible.

The chlorinated isocoumarin compound, ochratoxin A (OTA), together with some related derivatives (ochratoxins B, C, a, l) are produced byPenicillium verrucosumand by several spp. of Aspergillus, most notablyA. ochraceus. P. verrucosumis the principal source of OTA contamination of stored foods in temperate climates while Aspergillus spp. predominate in warmer countries. The major dietary sources of OTA are cereals but significant levels of contamination may be found in grape juice and red wine, coffee, cocoa, nuts, spices and dried fruits. Because of the chemical stability of OTA and long half-life in mammalian tissues, contamination may also carry over into pork and pig blood products and into beer. OTA is potently nephrotoxic and carcinogenic, the potency varying markedly between species and sexes; it is also teratogenic and immunotoxic. There have been different approaches to the risk assessment of OTA in different jurisdictions, largely arising from whether or not the carcinogenicity of OTA is considered to arise through a thresholded or non-thresholded mechanism. Consequently the tolerable intakes have variously been estimated at 100 ng/kg bw/week (JECFA), 1.5 to 5.7 ng/kg bw/day (Canada) and not more than 5 ng/kg bw/day (European Commission). These differences are also reflected in risk management measures that have been implemented or proposed with different maximum contamination levels being applied to different commodities and to the same commodity in different countries. Prevention of contamination at source is considered to be the most effective public health measure. There is also a need to harmonise the risk assessment and management processes to a greater extent than currently exist if barriers to trade are to be avoided.

Whole homogenates of Agaricus bisporus metabolised the mushroom hydrazine agaritine [beta-N-(gamma-L(+)glutamyl)-4-(hydroxymethyl) phenylhydrazine] to generate at least three metabolites. None of these metabolites, however, was the free hydrazine [4-(hydroxymethyl)phenylhydrazine], the postulated metabolite of agaritine believed to be formed as a result of the loss of the gamma-glutamyl group, the reaction being catalysed by gamma-glutamyltransferase. The three metabolites of agaritine displayed weak mutagenic activity towards Salmonella typhimurium strain TA104. 4-(Hydroxymethyl)phenylhydrazine, as the N'-acetyl derivative, was metabolised by mushroom tyrosinase to yield a number of metabolites that induced a mutagenic response in S. typhimurium TA104. Similar to N'-acetyl-4-(hydroxymethyl)phenylhydrazine, agaritine was extensively metabolised by the mushroom tyrosinase but, in contrast, the structurally related N'-acetyl-4-hydrazinobenzoic acid did not serve as substrate of this enzyme, implying a critical role for the hydroxymethyl group at the para-position. In conclusion, the current studies have demonstrated for the first time that: (a) whole mushroom homogenates readily metabolise agaritine but not to the postulated 4-(hydroxymethyl)phenylhydrazine; and (b) mushroom tyrosinase metabolises agaritine and N'-acetyl-4-(hydroxymethyl)phenylhydrazine, in the latter case forming genotoxic metabolites.

The fate of the mushroom hydrazine [14C]agaritine was investigated in the mouse and rat strains previously employed in carcinogenicity studies with the edible mushroom Agaricus bisporus. Agaritine was rapidly absorbed in both species, achieving higher blood levels in the mouse, but with similar area under the curve. Covalent binding of agaritine material to proteins was detected only in the liver and kidney, but the extent of binding was the same in the rat and mouse. Most of the radioactivity was excreted during the first 24 hours in both animal species: in the rat it was distributed equally between urine and feces, whereas in the mouse more of the radioactivity was excreted in the urine. No qualitative differences in the metabolic profile were evident, but quantitative differences were observed. Treatment of the urine with deconjugating enzymes did not reveal the presence of any conjugates. Agaritine, N'-acetyl-4-(hydroxymethyl)phenylhydrazine, and 4-(hydroxymethyl)benzene diazonium ion were not detected in the urine or in the plasma of either species. No mutagens or promutagens were detected by the Ames mutagenicity assay in the urine of either species after exposure to agaritine. Repeated administration of agaritine to rats and mice did not alter the urinary metabolic profile and excretion of radioactivity. Similarly, feeding mice a raw mushroom diet, according to the protocol employed in the carcinogenicity studies, did not modulate the excretion of radioactivity or the urinary metabolic pattern. No major species differences in the fate of agaritine in rat and mouse were noted that could provide a rationale for the carcinogenicity of A. bisporus in the mouse, but not in the rat.

The possibility that structurally unrelated food additives could show either joint actions or interactions has been assessed based on their potential to share common sites and mechanisms of action or common pathways of elimination. All food additives approved in the European Union and allocated numerical acceptable daily intake values were studied, initially based on the reports by the FAO-WHO Joint Expert Committee for Food Additives. Target organs were identified based on the effects reported at doses above the no-observed-adverse-effect level (NOAEL) in animal and human studies. The descriptions of the pathological and other changes reported were used to assess whether different additives, sharing the same target organ, would produce a common toxic effect. In all but a very few cases, the possibility of joint actions or interactions could be excluded on scientific grounds. The exceptions were on the liver (curcumin, thiabendazole, propyl gallate, and BHT), the kidney (diphenyl, o-phenylphenol, and ferrocyanide salts), the blood (azorubine and propyl gallate), and the thyroid (erythosine, thiabendazole, and nitrate). Toxicokinetic interactions were considered unlikely because of the low dosages involved, the diverse nature of the routes of metabolism and elimination, and the fact that enzyme induction or inhibition would have influenced selection of the NOAEL. Many of those additives which could not be excluded from showing joint actions or interactions would have low intakes; in some cases they were alternatives for the same application, thereby further lowering the combined intake. In consequence, joint actions or interactions between additives do not represent a significant health concern. (C) 2000 International Life Sciences Institute.

Rats maintained on green, black or decaffeinated black tea (2.5%, w/v) as their sole drinking fluid displayed higher hepatic CN- insensitive palmitoyl CoA oxidase activity than controls; the extent of increase was similar with the three types of tea. Morphological examination of the liver using electron microscopy revealed an increase in the number of peroxisomes in the tea-treated animals. The same treatment of the animals with green and black tea resulted in a similar rise in hepatic microsomal lauric acid hydroxylation. Analysis by HPLC of the aqueous tea extracts employed in the current study showed that the total flavanol content of the green variety was much higher than the black varieties, and confirmed the absence of caffeine in the decaffeinated black tea. It may be concluded from the present studies that neither caffeine nor flavanoids are likely to be responsible for the proliferation of peroxisomes observed in rats treated with tea.