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M Richold

Publications and source records attributed to M Richold.

At least 19 recordsLinked to original sources
PubMed1999

Report of workshop on the significance of excursions of intake above the ADI.

The acceptable daily intake (ADI) for humans was originally developed by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and defined as "an estimate of the amount of a food additive, expressed on a body weight basis, that can be ingested daily over a lifetime without appreciable health risk." JECFA has not provided any firm guidance on how to evaluate excursions of intake above the ADI, but WHO in 1987 stated that "because in most cases, data are extrapolated from life-time animal studies, the ADI relates to life-time use and provides a margin of safety large enough for toxicologists not to be particularly concerned about short-term use at exposure levels exceeding the ADI, providing the average intake over longer periods of time does not exceed it." In discussing short-term intakes in excess of recommended limits, JECFA in 1989 concluded that short-term exposures to levels exceeding the provisional tolerable weekly intake (PTWI) for a contaminant is not a cause of concern, provided the individual's intake averaged over longer periods of time does not exceed the level set. JECFA also stated that it was impossible to make a generalization concerning the length of time during which intakes in excess of the PTWI would be toxicologically detrimental. Any detrimental effect would depend upon the nature of the toxicity and the biological half-life of the chemical concerned. JECFA considered intakes of food additives in excess of the ADI less likely to occur and easier to control than in the case of contaminants which are allocated either a PTWI or a tolerable daily intake (TDI). The ILSI Europe Acceptable Daily Intake Task Force together with the Food Chemical Intake Task Force initiated a workshop which took place April 21-23, 1998, in Milan, Italy, in order to help identify what information would be needed, with what precision, and what is already available to evaluate the significance of excursions of intake above the ADI. The specific aims of the workshop were to address the following questions: By how much can the ADI be exceeded? For how long can excursions above the ADI be tolerated with respect to chronic toxicity, accumulation, and mechanisms of toxicity? What methods should be used to estimate intakes so that the estimates are relevant to the ADI? Do the same principles apply to contaminants that have TDI or PTWI values?

Animals↗
PubMed1999

Safety evaluation of phytosterol esters. Part 3. Two-generation reproduction study in rats with phytosterol esters--a novel functional food.

Phytosterol esters (PE) are intended for use as a novel food ingredient with plasma cholesterol lowering activity which works by inhibiting the absorption of cholesterol from the gut. Although PE are naturally present in the normal diet, the levels are insufficiently large to ensure lowering of plasma cholesterol levels. Therefore PE may be added to spreads to achieve the desired cholesterol lowering activity. As part of an extensive programme of safety evaluation studies a two-generation reproduction study has been conducted in Wistar rats, in which the possible effect of PE on male and female reproductive performance and on the growth and development of the offspring was studied. Rats were fed diets containing PE at levels of 0, 1.6, 3.2 and 8.1% (w/w) PE over two successive generations, and a wide range of reproductive and developmental parameters, including sexual maturation parameters and oestrous cycle length, were determined. Macroscopic and microscopic examinations were conducted including a histological examination of selected organs from F1- and F2-weanlings and from F0- and F1-parental animals. Daily clinical observations did not reveal any unusual findings. In both generations, no effects of PE were observed on pup mortality (calculated on litter basis), precoital time, mating index, male and female fertility index, female fecundity index, gestation index, duration of gestation, number of females with stillborn pups, post-implantation loss and pup development. Furthermore, PE had no effect on sexual maturation parameters (preputial separation and vaginal opening) and oestrous cycle length. In addition, there were no dose-related effects on selected organs following histological examination. In conclusion, dietary administration of up to 8.1% PE (equivalent to a dose of 2.5 to 9.1 g PE/kg body weight/day, dependent on the period of the study) during two generations had no effect on reproduction of parental F0- and F1-generation Wistar rats, nor on the development of the F1- and F2-pups, nor on the sexual maturation of the F1-weanlings. Therefore, a nominal dietary PE concentration of 8.1% (equivalent to a dose of 2.5-9.1 g PE/kg body weight/day or 1.54-5.62 g phytosterol/kg body weight/day dependent on the period of the study) was considered to be the no-observed-adverse-effect level following daily oral administration of PE for two successive generations.

Animals↗
PubMed1998

Boron exposure from consumer products.

For a natural substance that is mined and for which the world total production is in excess of 3 million tons, it would not be surprising to discover there is considerable exposure to boron (B) and its salts. Human exposure can arise from a variety of natural sources, such as soil and water, and artificially in soils via fertilizer and in waters via discharges through its use in household products and cosmetics, or via its use in pesticides, preservatives, and pharmaceuticals. Receiving waters can also obtain B through industrial usage. Indirect and probably insignificant consumer exposure can arise via the use of borates in glass products, flame retardants, and enamels, these applications comprising the major proportion of borate usage. The general intake of B via its presence in food and water is around 1-7 mg/d, but the range of intake values is large and depends on geographical region, dietary habits (with nuts, fresh and dried fruits, and wine providing particularly rich sources), as well as the method of analysis employed. Drinking waters typically contain <1 mg B/L, but the range is large, and some populations will be exposed to considerably more than 1 mg B/L. B via food and water represents the greatest source of exposure for the general consumer. Sodium borate and boric acid are widely used in consumer products, and perborate is used in detergents, but even though there is a high potential for exposure, the internal dose of B to consumers via its use in household and personal products is very low partly owing to insignificant amounts of dermal absorption across normal skin.

Adverse Drug Reaction Reporting Systems↗
PubMed1992

Absence of mutagenic activity in Salmonella and of clastogenic activity in CHO cells of Caramel Colours I, II, III and IV.

A total of 15 caramel colours were examined for genotoxic activity using the Salmonella typhimurium plate incorporation assay (Ames test). Five bacterial strains, TA1535, TA1537, TA1538, TA98 and TA100 were used in all the plate incorporation tests. Caramel colours can be divided into four classes, classification depending on the preparative method used. In this study, representatives of all four classes of caramel colour were tested for genotoxic potential in the Ames test, some of the caramel colours being tested both with and without a pre-incubation stage. None of the 15 caramel colours tested exhibited genotoxic potential in any of the five bacterial tester strains. The last two caramel colours tested, in the series of 15 [203-23-4 (Class II) and 311 (Class III)] were also assessed for clastogenic potential. For this test, cultures of CHO cells were exposed to the two caramel colours and metaphase preparations from these cultures examined for evidence of chromosomal aberrations. No evidence of chromosome damaging activity was observed.

Animals↗
PubMed1988

The genotoxicity of trenbolone, a synthetic steroid.

Trenbolone, a synthetic androgen is used as a growth promotant in animal husbandry. Because of its steroidal structure and properties it has been extensively evaluated in a series of in vitro and in vivo assays to assess its genotoxic and initiating properties. Both the parent molecule 17-beta-hydroxy-trenbolone and its metabolite 17-alpha-hydroxy-trenbolone, produced only in cattle, have been tested. 17-beta-hydroxy-trenbolone was not genotoxic in the Ames Salmonella/microsome assay, cytogenetics assays in human lymphocytes and CHO cells, a micronucleus assay in CHO cells, a DNA repair synthesis assay in HeLa cells, mammalian cell mutation assays with CHO and V79 cells, the mouse micronucleus assay, rat bone marrow or spermatogonial cytogenetics assays or in a test for initiators in the rat. In the mouse lymphoma cell mutation assay with L 5178Y TK+/- cells, equivocal responses were obtained, particularly at highly toxic concentrations. With 17-alpha-hydroxy-trenbolone a weak positive response was obtained in the L5178Y Tk +/- assay, particularly at highly toxic concentrations. Negative results were obtained in the Ames Salmonella/microsome assay, the cytogenetics assays using both human lymphocytes in vitro and rat bone marrow in vivo, the DNA repair assay and in the CHO mammalian cell mutation assay. It was also negative in the in vivo test for initiators. From this extensive battery of data, and also taking into account published data on trenbolone, it is concluded that 17-alpha-hydroxytrenbolone and 17-beta-hydroxy-trenbolone are devoid of genotoxic activity and are not initiators of cancer.

Animals↗
PubMed1983

Absence of mutagenic activity of WHR-1142A, lidamidine hydrochloride, in 4 short-term tests for mutagenic/carcinogenic potential.

WHR-1142A, lidamidine hydrochloride, an antidiarrhoeal agent, was tested for possible mutagenic/carcinogenic activity in the Ames Salmonella typhimurium/metabolic activation test, the micronucleus test, by analysis of metaphase chromosomes obtained from human lymphocytes grown in culture and in a cell transformation assay. No evidence of mutagenic/carcinogenic activity due to WHR-1142A, lidamidine hydrochloride, was found in any of the 4 tests.

Animals↗
PubMed1982

An evaluation of the mutagenic potential of 2-(2',4'-diaminophenoxy)ethanol using the micronucleus test.

The micronucleus test in mice was used to investigate the mutagenic potential of 2-(2',4'-diaminophenoxy)ethanol. The test compound was administered by oral gavage to CD-1 mice (ICR derived) as 2 equal dosages of 250,500 and 1000 mg/kg bodyweight. Bone-marrow smears were examined for the presence of micronucleated cells in 2000 polychromatic erythrocytes per animal. In addition, the ratio of normochromatic to polychromatic erythrocytes was scored to provide an indication of the toxicity of the test compound to bone marrow cells. No increase in the incidence of micronucleated polychromatic erythrocytes was observed for any group dosed with 2-(2',4'-diaminophenoxy)ethanol, although evidence of bone-marrow toxicity was observed at all 3 dosages.

Animals↗
PubMed1982

Bacterial mutagenicity studies on chloroform in vitro.

Chloroform was tested for mutagenicity in the Salmonella/microsome assay using five strains of Salmonella typhimurium. In view of previous reports describing the development of liver and kidney tumours in some experiments involving long-term administration of chloroform to rats and mice, the mutagenicity tests were carried out in the absence of any S-9 microsomal-enzyme preparation and in the presence of S-9 microsomal-enzyme preparations derived from (a) livers and (b) kidneys of rats and mice previously exposed to the microsomal-enzyme inducer Aroclor 1254. No evidence of potential mutagenicity was observed under any of the test conditions. To determine whether the findings might have been influenced by the volatility of the chloroform, the test organisms were exposed to chloroform vapour, but again chloroform gave no indication of potential mutagenicity. Taken in conjunction with already published data from mutagenicity studies with chloroform, it appears unlikely that the tumours observed in some long-term rodent studies are attributable to a genotoxic action of the compound.

Animals↗
PubMed1981

Some biochemical and pharmacological properties of an epoxide metabolite of alclofenac.

The properties of an epoxide metabolite of alclofenac have been investigated in a number of in vitro and in vivo tests. Alclofenac epoxide was shown to inhibit the activity of yeast alcohol dehydrogenase and form a conjugate with cysteine. The epoxide, but not alclofenac itself, showed mutagenic effects on strains of Salmonella typhimurium sensitive to alkylating agents, but had no effect on strains sensitive to intercalating agents. In addition the epoxide was active in a cell transformation assay using as a target Syrian hamster cells. No acute toxic reactions were observed in mice treated with alclofenac epoxide and the compound was devoid of analgesic and acute antiinflammatory activity. Alclofenac epoxide was found to be a sensitising agent in the guinea-pig when administered either by injection with complete Freud's adjuvant or topically as an ethanolic solution. It is postulated that the formation of the epoxide may explain some of the therapeutic and toxicological properties of alclofenac in man.

Alcohol Oxidoreductases↗
PubMed1981

Bacterial mutation test on plafibride.

N-2-(p-Chlorophenoxy)-isobutyryl-N'-morpholinomethylurea (plafibride, ITA 104) was tested for mutagenic activity of the Ames Salmonella/mammalian microsome test. Salmonella typhimurium strains TA 1535, TA 1537, TA 1538, TA 98 and TA 100 were employed. Two of these strains (TA 1535 and TA 100) are sensitive to base pair substitution mutagens, whilst the remaining three are sensitive to frame-shift mutagens. No evidence of mutagenic activity of plafibride was observed either in the presence or absence of a liver microsomal supplement.

Animals↗
PubMed1977

Metabolic studies in rats of 75Se incorporated in vivo into fish muscle.

1. [75Se]selenite of [75Se]selenomethionine was injected in to the coelomic cavity of fish. After 2 d or 14 d the muscle portion of the fish was removed and homogenized. The long-term fate in rats of an oral dose of each labelled homogenate was compared with that of an oral dose of [75Ee]selenite or [75Se]selenomethionine mixed with unlabelled fish homogenate. 2. Urinary and faecal radioactivity were measured during the 1st week and whole-body radioactivity was determined for 10 weeks. Rats were killed at weekly intervals for 4 weeks for analysis of tissue distribution of 75Se. 3. Intestinal absorption of 75Se given as labelled fish homogenate was less complete than that of 75Se mixed with unlabelled homogenate, and the absorption of 75Se from the 14 d-labelled fish homogenate derived from [75Se]selenite was less complete than that of 75Se from the other labelled homogenates. 4. Urinary excretion of absorbed 75Se in the first 7 d was in the range 5--8% absorbed dose and was slightly greater in the rats given 75Se as selenite or derived from selenite than in those given 75Se as selenomethionine or derived from selenomethionine. Endogenous faecal excretion of absorbed Se was similar in all groups, as also were tissue distribution of retained 75Se and long-term whole-body turnover rate. 5. The results of these studies are compared with those of earlier studies of the metabolism in rats of [75Se]selenomethionine, [75Se]selenite, [75Se]selenocystine and 75Se incorporated in vivo into rabbit kidney. There were differences in the initial utilization of 75Se from these various sources but after the 1st week 75Se from all sources appeared to be metabolized similarly, suggesting that for rats dietary Se of all forms is ultimately incorporated into the same metabolic pool.

Animal Nutritional Physiological Phenomena↗