RESUMEN
This report represents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluate the safety of various food additives, including flavouring agents, with a view to recommending acceptable daily intakes (ADIs) and to preparing specifications for identity and purity. The Committee also evaluated the risk posed by two food contaminants, with the aim of advising on risk management options for the purpose of public health protection. The first part of the report contains a general discussion of the principles governing the toxicological evaluation and assessment of intake of food additives (in particular flavouring agents) and contaminants. A summary follows of the Committee's evaluations of technical, toxicological and intake data for certain food additives (acidified sodium chlorite, asparaginase from Aspergillus oryzae expressed in Aspergillus oryzae, carrageenan and processed Eucheuma seaweed, cyclotetraglucose and cyclotetraglucose syrup, isoamylase from Pseudomonas amyloderamosa, magnesium sulfate, phospholipase A1 from Fusarium venenatum expressed in Aspergillus oryzae, sodium iron(III) ethylenediaminetetraacetic acid (EDTA) and steviol glycosides); eight groups of related flavouring agents (linear and branched-chain aliphatic, unsaturated, unconjugated alcohols, aldehydes, acids and related esters; aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances; simple aliphatic and aromatic sulfides and thiols; aliphatic acyclic dials, trials and related substances; aliphatic acetals; sulfur-containing heterocyclic compounds; aliphatic and aromatic amines and amides; and aliphatic alicyclic linear alpha, beta -unsaturated di- and trienals and related alcohols, acids and esters); and two food contaminants (aflatoxin and ochratoxin A). Specifications for the following food additives were revised: maltol and ethyl maltol, nisin preparation, pectins, polyvinyl alcohol, and sucrose esters of fatty acids. Specifications for the following flavouring agents were revised: maltol and ethyl maltol, maltyl isobutyrate, 3-acetyl-2,5-dimethylfuran and 2,4,5-trimethyl-delta-oxazoline (Nos 1482, 1506 and 1559), and monomenthyl glutarate (No. 1414), as well as the method of assay for the sodium salts of certain flavouring agents. Annexed to the report are tables summarizing the Committee's recommendations for intakes and toxicological evaluations of the food additives and contaminants considered.
Asunto(s)
Seguridad de Productos para el Consumidor , Aditivos Alimentarios/efectos adversos , Aditivos Alimentarios/análisis , Contaminación de Alimentos/análisis , Política Nutricional , Animales , Aromatizantes/efectos adversos , Aromatizantes/análisis , Colorantes de Alimentos/efectos adversos , Colorantes de Alimentos/análisis , Humanos , Medición de Riesgo , Gestión de Riesgos , Seguridad , Naciones Unidas , Organización Mundial de la SaludRESUMEN
Internationally acceptable norms need to incorporate sound science and consistent risk management principles in an open and transparent manner, as set out in the Agreement on the Application of Sanitary and Phytosanitary Measures (the SPS Agreement). The process of risk analysis provides a procedure to reach these goals. The interaction between risk assessors and risk managers is considered vital to this procedure. This paper reports the outcome of a meeting of risk assessors and risk managers on specific aspects of risk analysis and its application to international standard setting for food additives and contaminants. Case studies on aflatoxins and aspartame were used to identify the key steps of the interaction process which ensure scientific justification for risk management decisions. A series of recommendations were proposed in order to enhance the scientific transparency in these critical phases of the standard setting procedure.
RESUMEN
This paper discusses genotoxicity testing and data interpretation as applied in The Netherlands in the context of the regulation of chemicals. Guidelines were first formulated in 1981 and their use evolved in practice, on the basis of increasing experience at the national and international levels. The distinction between in vitro assays to detect intrinsic genotoxic properties and in vivo assays as a subsequent phase to show the realization of this potential in an intact organism has always been a cornerstone of the Dutch approach. Several critical aspects of the use of short-term genotoxicity tests in sequential schemes are discussed, such as their predictivity for carcinogenicity, the limited database concerning the performance of short-term in vivo assays, the relevance of devising separate strategies to test for possible carcinogenicity and germ cell mutagenicity, and the use of short-term tests to discriminate between genotoxic and non-genotoxic carcinogens. Examples are given of how short-term tests contributed to the toxicological evaluation of chemicals in The Netherlands.
Asunto(s)
Pruebas de Carcinogenicidad , Legislación de Medicamentos , Pruebas de Mutagenicidad , Animales , Humanos , Países Bajos , Factores de RiesgoRESUMEN
Within the scope of the preparation of Integrated Criteria Documents for priority compounds in The Netherlands, the possible health effects of oral and inhalatory exposure to asbestos for the general population were evaluated. It was concluded from the results of experiments in animals that exposure to asbestos by the oral route is not carcinogenic and is not expected to present a health risk to the general population. Inhaled asbestos, however, is distinctly carcinogenic to man, giving rise to lung tumours, and mesotheliomas of the pleura and peritoneum. Chrysotile asbestos appears to be less potent in inducing mesotheliomas than the amphiboles, but all types of asbestos appear to have a similar potency for inducing lung cancer. The risk of mesothelioma is not expected to be influenced by smoking, whereas the risk of lung cancer is expected to be ten times higher in smokers than in non-smokers exposed to the same asbestos concentrations. Risk-assessment models for the inhalatory route, for the general population, are based on linear non-threshold extrapolation of occupational exposure to much lower environmental concentrations. These models give only a rough approximation of the risk of environmental exposure to asbestos. In accordance with the Air Quality Guidelines of the World Health Organization (World Health Organization, 1987), it was estimated that an extra risk of lung cancer of one in 10(6) (in the general population, with 30% smokers) may be presented by lifetime exposure to asbestos fibres longer than 5 microns, measured by electron microscopy, at concentrations of 100-1000/m3. It was further estimated that an extra risk of mesothelioma of one in 10(6) may be presented by lifetime exposure to 10-100 amphibole fibres/m3 or to a range of 100-10000 chrysotile fibres/m3 (fibres longer than 5 microns). From the current asbestos concentrations, the risk of mesothelioma for the general population in The Netherlands appears to be negligible; the extra risk of lung cancer is expected to be higher than 1 in 10(6) near asbestos sources, whereas it appears to be negligible in background areas and in most large cities and industrial areas. However, it must be borne in mind that the validity of the risk figures given is difficult to judge.
Asunto(s)
Amianto/toxicidad , Encuestas Epidemiológicas , Humanos , Países Bajos , Factores de RiesgoRESUMEN
The vinyl monomer acrylamide (AA) was studied for its activity in a range of genotoxicity tests, including the Salmonella/microsome test, the fluctuation test using Klebsiella pneumoniae, the test for gene mutations at the TK and HPRT loci in L5178Y mouse lymphoma cells, tests for chromosomal aberrations and SCEs in V79 Chinese hamster cells, the sex-linked recessive lethal (SLRL) and somatic mutation and recombination (SMART) assays in Drosophila melanogaster and the mouse bone marrow micronucleus assay. AA showed genotoxic activity in most systems. The bacterial tests did not respond, in compliance with literature data; also in the Drosophila SLRL test, no significant increase in mutation rate was observed.
Asunto(s)
Acrilamidas/toxicidad , Bacterias/efectos de los fármacos , Células/efectos de los fármacos , Células Eucariotas/efectos de los fármacos , Mutágenos , Acrilamida , Animales , Bacterias/genética , Médula Ósea/efectos de los fármacos , Médula Ósea/ultraestructura , Línea Celular , Línea Celular Transformada/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Cromosomas/efectos de los fármacos , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/genética , Células Eucariotas/ultraestructura , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/genética , Ratones , Pruebas de Mutagenicidad/métodos , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genéticaRESUMEN
In the past two decades several incidents of environmental pollution have become known in which people might have been exposed to the contaminating substances. In the Netherlands the National Poison Control Centre, a department of the National Institute of Public Health and Environmental Protection, plays a distinct role in dealing with the health problems arising from these incidencts. The health risk assessment of an environmental incident may be facilitated by utilizing a logical predetermined sequence of decision steps in order to avoid inappropriate responses which could induce many untoward effects within the population of the contaminated area. As an example of this general approach, the handling of a recent incident with mercuric chloride is described.
Asunto(s)
Contaminantes Ambientales/toxicidad , Centros de Control de Intoxicaciones , Exposición a Riesgos Ambientales , Indicadores de Salud , Humanos , Cloruro de Mercurio/toxicidad , Países Bajos , Salud PúblicaRESUMEN
The genetic and embryotoxic effects of bis(tri-n-butyltin)oxide (TBTO) were evaluated in multiple in vivo and in vitro short-term tests preparatory to its potential wide use as a molluscicide in control of schistosomiasis. When tested in the rec assay in Bacillus subtilis, TBTO was not mutagenic and it did not induce reverse mutations in Klebsiella pneumoniae. Neither in the presence nor in the absecne of rat liver activation system did TBTO produce point mutations in Salmonella typhimurium strains TA1530, TA1535, TA1538, TA97, TA98 or TA100. TBTO was matagenic in strain TA100 in a fluctuation test, but only in the presence of rat liver S9 (Aroclor-induced). TBTO did not induce gene mutations in the yeast Schizosaccharomyces pombe, mitotic gene conversions in the yeast Saccharomyces cerevisiae, nor sister-chromatid exchange in Chinese hamster ovary cells in the presence or absence of rat or mouse liver S9. In the latter cells, structural chromosomal aberrations, endoreduplicated and polyploid cells were induced. TBTO did not induce gene mutations in V79 Chinese hamster cells (to 8-azaguanine-, ouabain- or 6-thioguanine-resistance) in the presence of a rat liver postmitochondrial fraction or in cell (hamster embryo cells and human and mouse epidermal keratinocyte)-mediated assays. In mouse lymphoma cells, TBTO did not induce 6-thioguanine- or BUdR-resistant mutations. As many tumour promoters inhibit metabolic cooperation between V79 Chinese hamster 6-thioguanine-resistant/-sensitive cells, TBTO was tested but showed no such activity. TBTO was examined for the induction of recessive lethal mutations in adult Berlin K male Drosophila melanogaster, either by feeding or by injection. Doses of 0.37 or 0.74 mM did not increase the number of X-linked recessive lethal mutations. An increased number of micronuclei was observed in the polychromatic erythrocytes of male BALB/c mice 48 h after a single oral dose of TBTO (60 mg/kg bw), while a lower dose (30 mg/kg bw) was ineffective. Neither of the two doses had induced micronuclei 30 h after treatment. The reproductive toxicity of TBTO was studied in NMRI mice. In a 10-day toxicity study, the LD50 and LD10 were 74 and 34 mg/kg bw, respectively. An increased frequency of cleft palates was seen in the fetuses of mice (compared with controls, 0.7%) treated orally during pregnancy with 11.7 mg/kg TBTO (7%), 23.4 mg/kg (24%) or 35 mg/kg (48%).(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Compuestos de Trialquiltina/farmacología , Anomalías Inducidas por Medicamentos/etiología , Animales , Bacterias/efectos de los fármacos , Línea Celular , Núcleo Celular/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas , Aberraciones Cromosómicas , Cricetinae , Cricetulus , Drosophila melanogaster/efectos de los fármacos , Desarrollo Embrionario y Fetal/efectos de los fármacos , Femenino , Fibroblastos/efectos de los fármacos , Conversión Génica/efectos de los fármacos , Genes Letales , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Moluscocidas/farmacología , Moluscocidas/toxicidad , Pruebas de Mutagenicidad , Embarazo , Ratas , Compuestos de Trialquiltina/toxicidad , Levaduras/efectos de los fármacosRESUMEN
Methyl bromide is commonly used as a soil fumigant in greenhouses. In the framework of a toxicological evaluation, it was tested for possible genotoxic properties in two bacterial test systems (the fluctuation test using Klebsiella pneumoniae and the plate test using Salmonella typhimurium TA100 and TA98), two systems using mammalian cells in vitro (forward mutations at the TK and HPRT loci in L5178Y mouse lymphoma cells and unscheduled DNA synthesis in primary rat-liver cells) and in the sex-linked recessive lethal test using Drosophila melanogaster. Methyl bromide was active in all tests except the DNA-repair assay. The results indicate a relatively low mutagenic efficiency of the compound, as expected from its alkylating properties.
Asunto(s)
Hidrocarburos Bromados/toxicidad , Mutación/efectos de los fármacos , Animales , Reparación del ADN/efectos de los fármacos , Drosophila melanogaster/efectos de los fármacos , Klebsiella pneumoniae/efectos de los fármacos , Linfoma/enzimología , Ratones , Pruebas de Mutagenicidad , Salmonella typhimurium/efectos de los fármacos , Timidina Quinasa/genéticaRESUMEN
As it is not known to what extent differential growth rates of induced mutants lead to over- and under-representation of mutants in treated populations and thereby affect the determination of mutant frequencies, the mutation induction in X-irradiated L5178Y mouse lymphoma cells was determined via two methods. The first method involves the standard protocol which may suffer from the effect of differential growth rates, while the second method is based upon the fluctuation test in which the differential growth rates can be actually measured. It appeared that the standard protocol led to a mutant frequency that was similar to the mutant frequency determined in the fluctuation test. Therefore, the standard protocol appears to lead to only a minor under-estimation if any. Substantial heterogeneity in growth rates of induced mutants was observed, but the mutants with a selective advantage appear largely to compensate for the mutants that are lost because of selective disadvantage. It was calculated that the chance for isolating the same mutant twice from a treated population had been increased 2.2-fold because of the observed differential growth rates. Therefore, our data indicate that the standard protocol does not lead to serious errors in the determination of mutant frequencies and in the sampling of mutants. The fluctuation tests were also used to determine the spontaneous mutation frequency per cell per generation. The mutation rate appeared more than 10-fold enhanced in X-irradiated cells which may be attributed to the induction of a process of untargeted mutagenesis in mammalian cells.
Asunto(s)
División Celular/efectos de la radiación , Leucemia L5178/genética , Leucemia Experimental/genética , Modelos Genéticos , Mutación , Animales , Leucemia L5178/patología , Ratones , Rayos XRESUMEN
L5178Y mouse lymphoma cells were treated with the mismatching agent 6-hydroxy-aminopurine (HAP), a base analogue known to produce forward and reverse mutations in bacteria. Mutants with the phenotype deficient in hypoxanthine guanine phosphoribosyl transferase (HPRT) were selected in 6-thoiguanine(TG)-containing medium and isolated. Reverse mutations to the HPRT-proficient phenotype occurred both spontaneously and after treatment with ethyl nitrosourea (ENU), which suggested that the initial HAP treatment had induced point mutations at the HPRT locus. Reconstruction experiments, in which a small number of wild-type cells together with different numbers of mutant cells were seeded in HAT medium, indicated that densities up to 10(6) cells per ml can be used for the selection of revertants. Optimal expression of induced revertants was obtained two days after treatment. The dose-response relationship for induction of reverse mutations by ENU appears not to deviate from linearity. The highest revertant frequency observed was 3.3 x 10(-5) at an ENU concentration of 1 mM. The spontaneous reversion frequency per generation -- based on 3 spontaneous revertants -- was estimated to be 1.3 x 10(-9). All revertants were indistinguishable from the parental wild-type line with respect to the activity as well as the electrophoretic mobility of HPRT.
Asunto(s)
Hipoxantina Fosforribosiltransferasa/genética , Leucemia L5178/genética , Leucemia Experimental/genética , Mutación , Animales , Línea Celular , Células Clonales/citología , Células Clonales/enzimología , Etilnitrosourea/farmacología , Ratones , Mutágenos , Mutación/efectos de los fármacos , FenotipoRESUMEN
A series of 2 haloethanols and 3 epoxides was investigated in 3 mutagenicity test systems, namely (1) the fluctuation test in Klebsiella pneumoniae, (2) the sex-linked recessive lethal test in Drosophila melanogaster, and (3) the HGPRT test with L5178Y mouse lymphoma cells. The order of mutagenic potency was, in Klebsiella: glycidaldehyde greater than 2-bromoethanol = epichlorohydrin greater than 1,2-epoxybutane greater than 2-chloroethanol; in Drosophila: glycidaldehyde = epichlorohydrin greater than 1,2-epoxybutane; in mouse lymphoma cells: epichlorohydrin greater than 1,2-epoxybutane. The haloethanols were non-mutagenic in Drosophila. 2-Chloroethanol and glycidaldehyde were negative in mouse lymphoma cells. The high mutagenic potency of epichlorohydrin as compared with 1,2-epoxybutane was consistent in all systems, and with published data.
Asunto(s)
Aldehídos/farmacología , Clorhidrinas/farmacología , Epiclorhidrina/farmacología , Compuestos Epoxi/farmacología , Etanol/análogos & derivados , Éteres Cíclicos/farmacología , Etilenclorhidrina/farmacología , Mutágenos/farmacología , Animales , Drosophila melanogaster/efectos de los fármacos , Etanol/farmacología , Femenino , Klebsiella pneumoniae/efectos de los fármacos , Leucemia L5178/genética , Masculino , Ratones , Pruebas de MutagenicidadAsunto(s)
Drosophila melanogaster/genética , Metanosulfonato de Etilo/farmacología , Pruebas de Mutagenicidad/métodos , Uretano/farmacología , Animales , Deleción Cromosómica , Sinergismo Farmacológico , Femenino , Genes Letales , Genes Recesivos , Masculino , Mutágenos , Aberraciones Cromosómicas Sexuales , Factores de TiempoAsunto(s)
Pruebas de Mutagenicidad , Toxicología , Animales , Humanos , Países Bajos , Proyectos de InvestigaciónRESUMEN
The possibility that ethionine, the ethyl analog of methionine and potent liver carcinogen, exerts its action by blocking the methylation of DNA and thereby rendering the post-replicative methylation instructed error-avoidance system inoperative was investigated. While the results are not directly supportive for the existence of such a repair system in V79 Chinese hamster cells, effects of ethionine were found. Following the exposure of ethionine-treated cells to EMS an increase in cell killing and a decrease in mutation induction was observed. The base analog, 6-hydroxyaminopurine, was shown to be clearly mutagenic in the mammalian cells and in the presence of ethinine a drastic decrease in mutant frequency was observed. Ethionine itself did not appear mutagenic over the entire dose range tested (1-1000 micrograms/ml).
Asunto(s)
Etionina/farmacología , Mutágenos , 2-Aminopurina/análogos & derivados , 2-Aminopurina/farmacología , Animales , Línea Celular , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Metanosulfonato de Etilo/farmacología , PulmónRESUMEN
Molecular dosimetry studies were carried out to measure the extent of binding of radio-labeled ethyl groups to the DNA of Escherichia coli, V79 Chinese hamster cells and L5178Y mouse lymphoma cells treated with ethyl methanesulfonate (EMS). The results show that (1) the amount of ethylation of the DNA is similar in these cells when treatment conditions are identical, (2) the relationship between dose to DNA (ethylations per nucleotide) versus exposure (mM applied concentration) is non-linear in the sense that less alkylation of the DNA is observed at the higher exposures than would be predicted on the basis of proportionality between dose to DNA and exposure, and (3) the non-linearity of the genetic response in the bacterial cells is not reflected in a non-linearity of the alkylation of the DNA in those cells. Quantitative comparison of the frequencies of gene mutations in the various systems shows that the mutation frequency per unit of DNA alkylation is heterogeneous among the mammalian cell systems and that the frequencies observed in the bacterial cells fall within the range observed with mammalian cells. Alkylation of the DNA in the bone marrow, testis and liver of Swiss random-bred mice was also measured. The results support the conclusion that the distribution of the compound to the various tissues is rapid and probably uniform. Quantitative assessment of the cytological data (micronuclei, sister-chromatid exchanges, etc.) on the basis of dose was not as useful because of the low efficiency of EMS for inducing cytologically observable damage.
Asunto(s)
Metanosulfonato de Etilo/farmacología , Mutágenos , Animales , Línea Celular , Cricetinae , Cricetulus , ADN/genética , ADN Bacteriano/genética , Relación Dosis-Respuesta a Droga , Escherichia coli/efectos de los fármacos , Frecuencia de los Genes , Leucemia L5178/genética , Pulmón , RatonesRESUMEN
Morphine hydrochloride was tested for its ability to induce sex-linked recessive lethal mutations, II--III translocations or dominant lethal mutations, in Drosophila melanogaster. The results provide no evidence for the induction of any of these types of genetic damage in this system
Asunto(s)
Aberraciones Cromosómicas , Morfina/farmacología , Mutación , Animales , Drosophila melanogaster , Genes Dominantes , Genes Letales , Genes Recesivos , Ligamiento Genético , Larva , Masculino , Cromosomas SexualesRESUMEN
Four structural analogues of the antischistosomal drug hycanthone, indicated as IA-3, IA-4, IA-5, and IA-6, were tested for their ability to induce sex-linked recessive lethal mutations in Drosophila melanogaster. The compounds were administered to adult male flies, by abdominal injection or by feeding. Although in some cases a slight enhancement of the mutation frequency was observed, the analogues tested are considerably less mutagenic in this system than hycanthone itself, the concentrations applied being approximately of equal molarity.
Asunto(s)
Drosophila melanogaster/efectos de los fármacos , Mutágenos , Tioxantenos/análogos & derivados , Animales , Genes Letales , Genes Recesivos , Ligamiento Genético , Cromosomas SexualesRESUMEN
The development of a system for the detection of somatic cell mutation to hypoxanthine-guanine-phosphoribosyl-transferase (HGPRT) (EC 2.4.2.8) deficiency in L5178Y mouse lymphoma cells is described. The selection of mutant cells was not influenced by the concentration of the selective agent 6-thioguanine (6-TG). In addition, all the mutants selected, spontaneous as well as induced ones, showed a complete loss of HGPRT activity. In reconstruction experiments, in which mutant cells were mixed with wild-type cells, the recovery of mutant cells was only markedly influenced when wild-type cells were seeded in a cell density ten times higher than the one, 5-10(4) cells/ml, used in subsequent induction experiments. X-irradiation and treatment with ethyl methanesulfonate (EMS) increased in the mutation rate above the spontaneous background. A clear-cut dose-dependent mutagenic effect after exposure to X-rays was measured. The rate of induced mutations at the HGPRT locus in lymphoma cells was 1-3-10(-7) per R, as determined after exposures of 200, 300, 400, 500 and 600 R. The time the cells needed to express their mutations was much longer than 48 h. Further study of this phenomenon showed that the optimal expression time for TGr-resistant mutants in L5178Y cells was 6 to 7 days. No indication for a dose-dependent effect on the optimal expression of the mutants was found.