RESUMEN
OBJECTIVE: The management measures to contain the SARS-CoV-2 pandemic in 2020 has upset the organization of society, particularly the organization of the health system. We aimed to analyze the evolution of induced abortions in the Paris region in 2020 and to highlight the impact of the first confinement. METHOD: Data from the National Health Insurance plan was analyzed to study abortion during the pandemic period (2020) compared to the previous four years (2016-2019). In 2020 the indicators of induced abortion were studied monthly to highlight the impact of the confinement. The age of women, the method used to terminate the pregnancy, the gestational age at the time of the abortion and the area of residence of women were analyzed. RESULTS: After five consecutive years of increasing abortion rates, our result showed that the number of abortions declined from 53,601 in 2019 to 50,615 in 2020 (decline of 5.6%). The abortion rate was 17.3 per 1,000 women aged 15-49 in 2019 and 16.3 in 2020. This drop was observed within 4 weeks following the first confinement. It concerned particularly abortions carried out in the hospital context and abortions of young women (< 25 years old). In 2020 the rate of medical abortions increased compared to the 4 years preceding the pandemic. The use of local anesthesia for surgical abortions also increased in the Paris region during the first confinement. Our study showed a fewer proportion of late abortion (over 12 weeks of amenorrhea) in 2020. This analysis also showed a drop in the number of births in the eight to nine months that followed the first confinement in the Paris region. DISCUSSION AND CONCLUSION: The COVID-19 pandemic has had health consequences not directly attributable to the virus. In terms of reproduction, the pandemic, particularly the first lockdown, has been associated to a decrease in conceptions resulting in a decrease in the number pregnancies including those ending in induced abortion or childbirth. The reduction of abortions is observed in the four weeks following the first confinement and the fall in the birth rate in the following 8 to 9 months.
Asunto(s)
Aborto Inducido , COVID-19 , Embarazo , Femenino , Humanos , Adulto , Aborto Legal , Pandemias , COVID-19/epidemiología , Vigilancia de la Población , SARS-CoV-2 , Control de Enfermedades TransmisiblesRESUMEN
This publication is the thirteenth in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Since then, the number of flavoring substances has grown to more than 2600 substances. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of aliphatic and aromatic terpene hydrocarbons as flavoring ingredients are evaluated. The group of aliphatic and aromatic terpene hydrocarbons was reaffirmed as GRAS (GRASr) based, in part, on their self-limiting properties as flavoring substances in food; their rapid absorption, metabolic detoxication, and excretion in humans and other animals; their low level of flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies and the lack of significant genotoxic potential.
Asunto(s)
Aromatizantes/análisis , Terpenos/análisis , Animales , Aromatizantes/farmacocinética , Aromatizantes/toxicidad , Humanos , Terpenos/farmacocinética , Terpenos/toxicidad , Pruebas de Toxicidad/métodos , Estados UnidosRESUMEN
This publication is the 12th in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Since then, the number of flavoring substances has grown to more than 2200 chemically-defined substances. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, toxicodynamics and toxicology. Scientific data relevant to the safety evaluation for the use of aliphatic, linear alpha,beta-unsaturated aldehydes and structurally related substances as flavoring ingredients are evaluated. The group of substances was reaffirmed as GRAS (GRASr) based, in part, on their self-limiting properties as flavoring substances in food; their low level of flavor use; the rapid absorption and metabolism of low in vivo concentrations by well-recognized biochemical pathways; adequate metabolic detoxication at much higher levels of exposure in humans and animals; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies. While some of the compounds described here have exhibited positive in vitro genotoxicity results, evidence of in vivo genotoxicity and carcinogenicity occurs only under conditions in which animals are repeatedly and directly exposed to high irritating concentrations of the aldehyde. These conditions are not relevant to humans who consume alpha,beta-unsaturated aldehydes as flavor ingredients at low concentrations distributed in a food or beverage matrix.
Asunto(s)
Aldehídos/toxicidad , Aromatizantes/toxicidad , Aldehídos/análisis , Aldehídos/química , Aldehídos/farmacocinética , Animales , Carcinógenos/análisis , Carcinógenos/toxicidad , Aromatizantes/análisis , Aromatizantes/química , Aromatizantes/farmacocinética , Análisis de los Alimentos , Humanos , Mutágenos/análisis , Mutágenos/toxicidad , Reproducción/efectos de los fármacosRESUMEN
The OECD Health Effects Test Guidelines (TGs) provide guidance concerning the use of methods for the identification and characterization of hazards from chemical substances. These TGs are largely based on tests in routine use for many years and are known to yield information relevant to various types of toxicity. They have proven their value in practice and will remain of paramount importance for decades to come. However, the TGs describe mostly animal assays, and there is an increasingly strong urge to reduce animal testing on ethical grounds. In addition, assessment procedures are generally considered too slow and too rigid, which has resulted in elaborate testing of a relatively small number of chemicals, while virtually nothing is known about the vast majority of compounds. The major objectives of Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) are to improve the knowledge about the properties and use of chemicals and to speed up the procedure of risk assessment. The REACH text contains information requirements that can be met by OECD TGs but REACH also provides rules for adaptation of the standard testing regime. Also, various components of "Intelligent Testing Strategies" are described in order to limit animal testing. This paper briefly describes the OECD TGs for inhalation toxicity studies, including those in preparation, and their role in future hazard identification. This will be discussed in relation to the evaluation of the safety of thousands of chemicals in a relatively short period of time and scientific developments, including the use of alternatives to animal testing.
Asunto(s)
Alternativas a las Pruebas en Animales/legislación & jurisprudencia , Guías como Asunto , Exposición por Inhalación , Pruebas de Toxicidad/métodos , Xenobióticos/toxicidad , Animales , Unión Europea , Regulación Gubernamental , Medición de Riesgo , Técnicas de Cultivo de Tejidos , Xenobióticos/administración & dosificaciónRESUMEN
The threshold of toxicological concern (TTC) has been used for the safety assessment of packaging migrants and flavouring agents that occur in food. The approach compares the estimated oral intake with a TTC value derived from chronic oral toxicity data for structurally-related compounds. Application of the TTC approach to cosmetic ingredients and impurities requires consideration of whether route-dependent differences in first-pass metabolism could affect the applicability of TTC values derived from oral data to the topical route. The physicochemical characteristics of the chemical and the pattern of cosmetic use would affect the long-term average internal dose that is compared with the relevant TTC value. Analysis has shown that the oral TTC values are valid for topical exposures and that the relationship between the external topical dose and the internal dose can be taken into account by conservative default adjustment factors. The TTC approach relates to systemic effects, and use of the proposed procedure would not provide an assessment of any local effects at the site of application. Overall the TTC approach provides a useful additional tool for the safety evaluation of cosmetic ingredients and impurities of known chemical structure in the absence of chemical-specific toxicology data.
Asunto(s)
Cosméticos/toxicidad , Seguridad , Pruebas de Toxicidad , Administración Cutánea , Administración Oral , Cosméticos/administración & dosificación , Técnicas de Apoyo para la Decisión , Árboles de Decisión , Humanos , Nivel sin Efectos Adversos ObservadosRESUMEN
This publication is the 11th in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. The list of GRAS substances has now grown to more than 2100 substances. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. In this monograph, a detailed interpretation is presented on the renal carcinogenic potential of the aromatic secondary alcohol alpha-methylbenzyl alcohol, aromatic ketone benzophenone, and corresponding alcohol benzhydrol. The relevance of these effects to the flavor use of these substances is also discussed. The group of aromatic substituted secondary alcohols, ketones, and related esters was reaffirmed as GRAS (GRASr) based, in part, on their rapid absorption, metabolic detoxication, and excretion in humans and other animals; their low level of flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies and the lack of significant genotoxic and mutagenic potential.
Asunto(s)
Alcoholes/toxicidad , Seguridad de Productos para el Consumidor , Aromatizantes/toxicidad , Industria de Alimentos/normas , Cetonas/toxicidad , Alcoholes/farmacocinética , Alcoholes/normas , Animales , Benzofenonas/farmacocinética , Benzofenonas/normas , Benzofenonas/toxicidad , Ésteres , Aromatizantes/farmacocinética , Aromatizantes/normas , Humanos , Cetonas/farmacocinética , Cetonas/normas , Nivel sin Efectos Adversos Observados , Alcohol Feniletílico/análogos & derivados , Alcohol Feniletílico/farmacocinética , Alcohol Feniletílico/normas , Alcohol Feniletílico/toxicidad , Pruebas de Toxicidad , Estados Unidos , United States Food and Drug AdministrationRESUMEN
This publication is the ninth in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of phenethyl alcohol, aldehyde, acid, and related acetals and esters as flavoring ingredients is evaluated. The group of phenethylalcohol, aldehyde, acid, and related acetals and esters was reaffirmed as GRAS (GRASr) based, in part, on their self-limiting properties as flavoring substances in food, their rapid absorption, metabolic detoxication, and excretion in humans and other animals, their low level of flavor use, the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies and the lack of significant genotoxic and mutagenic potential. This evidence of safety is supported by the fact that the intake of phenethyl alcohol, aldehyde, acid, and related acetals and esters as natural components of traditional foods is greater than their intake as intentionally added flavoring substances.
Asunto(s)
Acetaldehído/análogos & derivados , Aromatizantes/toxicidad , Industria de Alimentos , Fenilacetatos/toxicidad , Alcohol Feniletílico/toxicidad , United States Food and Drug Administration/legislación & jurisprudencia , Acetaldehído/farmacocinética , Acetaldehído/toxicidad , Acetales , Animales , Ésteres , Aromatizantes/farmacocinética , Aromatizantes/normas , Humanos , Fenilacetatos/farmacocinética , Alcohol Feniletílico/análogos & derivados , Alcohol Feniletílico/farmacocinética , Pruebas de Toxicidad , Estados Unidos , United States Food and Drug Administration/normasRESUMEN
This publication is the eighth in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of benzyl derivatives as flavoring ingredients is evaluated. The group of benzyl derivatives was reaffirmed as GRAS (GRASr) based, in part, on their self-limiting properties as flavoring substances in food; their rapid absorption, metabolic detoxication, and excretion in humans and other animals, their low level of flavor use, the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies and the lack of significant genotoxic and mutagenic potential. This evidence of safety is supported by the fact that the intake of benzyl derivatives as natural components of traditional foods is greater than their intake as intentionally added flavoring substances.
Asunto(s)
Benzaldehídos/toxicidad , Ácido Benzoico/toxicidad , Alcohol Bencilo/toxicidad , Aromatizantes/toxicidad , Industria de Alimentos , United States Food and Drug Administration/legislación & jurisprudencia , Animales , Benzaldehídos/farmacocinética , Ácido Benzoico/farmacocinética , Alcohol Bencilo/farmacocinética , Aromatizantes/farmacocinética , Aromatizantes/normas , Humanos , Pruebas de Toxicidad , Estados Unidos , United States Food and Drug Administration/normasRESUMEN
This publication is the ninth in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of hydroxy- and alkoxy-substituted benzyl derivatives as flavoring ingredients is evaluated. The group of hydroxy- and alkoxy-benzyl derivatives was reaffirmed as GRAS (GRASr) based, in part, on their self-limiting properties as flavoring substances in food; their rapid absorption, metabolic detoxication, and excretion in humans and other animals; their low level of flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies and the lack of significant genotoxic and mutagenic potential. This evidence of safety is supported by the fact that the intake of hydroxy- and alkoxy-substituted benzyl derivatives as natural components of traditional foods is greater than their intake as intentionally added flavoring substances.
Asunto(s)
Alcoholes , Compuestos de Bencilo/toxicidad , Aromatizantes/toxicidad , Industria de Alimentos , United States Food and Drug Administration/legislación & jurisprudencia , Animales , Compuestos de Bencilo/farmacocinética , Aromatizantes/farmacocinética , Aromatizantes/normas , Humanos , Pruebas de Toxicidad , Estados Unidos , United States Food and Drug Administration/normasRESUMEN
A scientifically based guide has been developed to evaluate the safety of naturally occurring mixtures, particularly essential oils, for their intended use as flavor ingredients. The approach relies on the complete chemical characterization of the essential oil and the variability of the composition of the oil in the product intended for commerce. Being products of common plant biochemical pathways, the chemically identified constituents are organized according to a limited number of well-established chemical groups called congeneric groups. The safety of the intake of the each congeneric group from consumption of the essential oil is evaluated in the context of data on absorption, metabolism, and toxicology of members of the congeneric group. The intake of the group of unidentified constituents is evaluated in the context of the consumption of the essential oil as a food, a highly conservative toxicologic threshold, and toxicity data on the essential oil or an essential oil of similar chemotaxonomy. The flexibility of the guide is reflected in the fact that high intake of major congeneric groups of low toxicologic concern will be evaluated along with low intake of minor congeneric groups of significant toxicological concern (i.e., higher structural class). The guide also provides a comprehensive evaluation of all congeneric groups and constituents that account for the majority of the composition of the essential oil. The overall objective of the guide is to organize and prioritize the chemical constituents of an essential oil in order that no reasonably possible significant risk associated with the intake of essential oil goes unevaluated. The guide is, however, not intended to be a rigid checklist. The Flavor and Extract Manufacturers Association (FEMA) Expert Panel will continue to evaluate each essential oil on a case by case basis applying their scientific judgment to insure that each natural flavor complex is exhaustively evaluated.
Asunto(s)
Seguridad de Productos para el Consumidor , Aromatizantes/efectos adversos , Aceites Volátiles/efectos adversos , Animales , Evaluación de Medicamentos , Aromatizantes/química , Aromatizantes/metabolismo , Industria de Alimentos , Tecnología de Alimentos , Humanos , Aceites Volátiles/análisis , Aceites Volátiles/metabolismo , Estados UnidosRESUMEN
Recent developments in hazard identification and risk assessment of chemical mixtures are reviewed. Empirical, descriptive approaches to study and characterize the toxicity of mixtures have dominated during the past two decades, but an increasing number of mechanistic approaches have made their entry into mixture toxicology. A series of empirical studies with simple chemical mixtures in rats is described in some detail because of the important lessons from this work. The development of regulatory guidelines for the toxicological evaluation of chemical mixtures is discussed briefly. Current issues in mixture toxicology include the adverse health effects of ambient air pollution; the application of such modern, sophisticated methodologies as genomics, bioinformatics, and physiologically based pharmacokinetic modeling; and databases for mixture toxicity. Finally, the state of the art of our knowledge on the potential adverse health effects of combined exposures to chemicals and non-chemical stressors (noise, heat/cold, microorganisms, immobilization, restraint, or transportation), research initiatives in these fields, and the development of an indicator for the cumulative health impact of multiple environmental exposures are discussed.
Asunto(s)
Exposición a Riesgos Ambientales/efectos adversos , Toxicología/métodos , Xenobióticos/toxicidad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Humanos , Modelos Estadísticos , Medición de Riesgo , Seguridad , Análisis de Secuencia de Proteína , Relación Estructura-Actividad , Xenobióticos/farmacocinéticaRESUMEN
Natural flavour complexes (NFCs) are chemical mixtures obtained by applying physical separation methods to botanical sources. Many NFCs are derived from foods. In the present paper, a 12-step procedure for the safety evaluation of NFCs, 'the naturals paradigm', is discussed. This procedure, which is not intended to be viewed as a rigid check list, begins with a description of the chemical composition of the commercial product, followed by a review of the data on the history of dietary use. Next, each constituent of an NFC is assigned to one of 33 congeneric groups of structurally related substances and to one of three classes of toxic potential, each with its own exposure threshold of toxicological concern. The group of substances of unknown structure is placed in the class of greatest toxic potential. In subsequent steps, for each congeneric group the procedure determines the per capita intake, considers metabolic pathways and explores the need and availability of toxicological data. Additional toxicological and analytical data may be required for a comprehensive safety evaluation. The procedure concludes with an evaluation of the NFC in its entirety, also considering combined exposure to congeneric groups. The first experiences with the use of this procedure are very promising. Future safety evaluations of larger numbers of NFCs will indicate the usefulness of the system, either in its present form or in a form modified on the basis of experience.
Asunto(s)
Factores Biológicos/toxicidad , Aromatizantes/toxicidad , Animales , Factores Biológicos/efectos adversos , Factores Biológicos/química , Factores Biológicos/normas , Mezclas Complejas/efectos adversos , Mezclas Complejas/química , Mezclas Complejas/normas , Mezclas Complejas/toxicidad , Elettaria/toxicidad , Aromatizantes/efectos adversos , Aromatizantes/química , Aromatizantes/normas , Humanos , Aceites de Plantas/toxicidadRESUMEN
This publication is the seventh in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers' Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavouring substances under conditions of intended use. In this review, scientific data relevant to the safety evaluation of the allylalkoxybenzene derivatives methyl eugenol and estragole is critically evaluated by the FEMA Expert Panel. The hazard determination uses a mechanism-based approach in which production of the hepatotoxic sulfate conjugate of the 1'-hydroxy metabolite is used to interpret the pathological changes observed in different species of laboratory rodents in chronic and subchronic studies. In the risk evaluation, the effect of dose and metabolic activation on the production of the 1'-hydroxy metabolite in humans and laboratory animals is compared to assess the risk to humans from use of methyl eugenol and estragole as naturally occurring components of a traditional diet and as added flavouring substances. Both the qualitative and quantitative aspects of the molecular disposition of methyl eugenol and estragole and their associated toxicological sequelae have been relatively well defined from mammalian studies. Several studies have clearly established that the profiles of metabolism, metabolic activation, and covalent binding are dose dependent and that the relative importance diminishes markedly at low levels of exposure (i.e. these events are not linear with respect to dose). In particular, rodent studies show that these events are minimal probably in the dose range of 1-10 mg/kg body weight, which is approximately 100-1000 times the anticipated human exposure to these substances. For these reasons it is concluded that present exposure to methyl eugenol and estragole resulting from consumption of food, mainly spices and added as such, does not pose a significant cancer risk. Nevertheless, further studies are needed to define both the nature and implications of the dose-response curve in rats at low levels of exposure to methyl eugenol and estragole.
Asunto(s)
Eugenol/análogos & derivados , Eugenol/toxicidad , Aromatizantes/toxicidad , Animales , Biotransformación , Eugenol/química , Eugenol/farmacocinética , Femenino , Aromatizantes/química , Aromatizantes/farmacocinética , HumanosRESUMEN
This paper addresses major developments in the safety evaluation of chemical mixtures during the past 15 years, reviews today's state of the art of mixture toxicology, and discusses challenges ahead. Well-thought-out tailor-made mechanistic and empirical designs for studying the toxicity of mixtures have gradually substituted trial-and-error approaches, improving the insight into the testability of joint action and interaction of constituents of mixtures. The acquired knowledge has successfully been used to evaluate the safety of combined exposures and complex mixtures such as, for example, the atmosphere at hazardous waste sites, drinking water disinfection by-products, natural flavouring complexes, and the combined intake of food additives. To consolidate the scientific foundation of mixture toxicology, studies are in progress to revisit the biological concepts and mathematics underlying formulas for low-dose extrapolation and risk assessment of chemical mixtures. Conspicuous developments include the production of new computer programs applicable to mixture research (CombiTool, BioMol, Reaction Network Modelling), the application of functional genomics and proteomics to mixture studies, the use of nano-optochemical sensors for in vivo imaging of physiological processes in cells, and the application of optical sensor micro- and nano-arrays for complex sample analysis. Clearly, the input of theoretical biologists, biomathematicians and bioengineers in mixture toxicology is essential for the development of this challenging branch of toxicology into a scientific subdiscipline of full value.
Asunto(s)
Toxicología/métodos , Xenobióticos/toxicidad , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/toxicidad , Animales , Interacciones Farmacológicas , Alimentos/efectos adversos , Humanos , Modelos Estadísticos , Salud Pública , Toxicología/estadística & datos numéricos , Abastecimiento de Agua/análisisRESUMEN
This paper presents a test strategy to detect interactive effects between several mycotoxins using a DNA synthesis inhibition assay in L929 cells. The joint action of the Fusarium mycotoxins T-2 toxin (T2), deoxynivalenol (DON), nivalenol (NIV), zearalenone (ZEA) and fumonisin (FB1) was studied in a tiered approach. In the first stage, the mycotoxins were tested either jointly in a five-compound mixture, or individually. At the highest dose level, the mixture showed a clear less than additive action of the mycotoxins, as compared to the effects of the five individual compounds, whereas at lower dose levels the mycotoxins behaved additive. In the second stage, the non-additivity as established in the first experiment was further analyzed with a central composite design to detect interactions between specific mycotoxins in the mixture. This experiment confirmed less than additivity for five of the mixes tested. However, it also revealed four significant synergistic interactions between mycotoxins. Finally, two interactions that were established in stage 2 were further studied in full factorial designs involving two mycotoxins. One of the interactions observed in the central composite design was retrieved whereas the other two-factor interaction was not. It was concluded that several classes of mycotoxins when present simultaneously in a mixture might show interaction. The effect of the mixture cannot be predicted solely on the basis of the effect of the individual compounds.
Asunto(s)
Fusarium/química , Micotoxinas/toxicidad , Algoritmos , Animales , Línea Celular , ADN/biosíntesis , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Modelos Lineales , Ratones , Inhibidores de la Síntesis del Ácido Nucleico/toxicidadRESUMEN
This is the fifth in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually taking into account the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of pyrazine derivatives as flavoring ingredients is evaluated.
Asunto(s)
Aromatizantes/farmacocinética , Pirazinas/farmacocinética , Seguridad , Animales , Carcinógenos/química , Carcinógenos/farmacocinética , Carcinógenos/toxicidad , Aromatizantes/química , Aromatizantes/toxicidad , Industria de Alimentos , Humanos , Ratones , Pirazinas/química , Pirazinas/toxicidad , Ratas , Valores de Referencia , Pruebas de ToxicidadRESUMEN
Studies on the irritative effects of acetone vapor in humans and experimental animals have revealed large differences in the lowest acetone concentration found to be irritative to the respiratory tract and eyes. This has brought on much confusion in the process of setting occupational exposure limits for acetone. A literature survey was carried out focusing on the differences in results between studies using subjective (neuro)behavioral methods (questionnaires) and studies using objective measurements to detect odor and irritation thresholds. A critical review of published studies revealed that the odor detection threshold of acetone ranges from about 20 to about 400 ppm. Loss of sensitivity due to adaptation and/or habituation to acetone odor may occur, as was shown in studies comparing workers previously exposed to acetone with previously unexposed subjects. It further appeared that the sensory irritation threshold of acetone lies between 10,000 and 40,000 ppm. Thus, the threshold for sensory irritation is much higher than the odor detection limit, a conclusion that is supported by observations in anosmics, showing a ten times higher irritation threshold level than the odor threshold found in normosmics. The two-times higher sensory irritation threshold observed in acetone-exposed workers compared with previously nonexposed controls can apart from adaptation be ascribed to habituation. An evaluation of studies on subjectively reported irritation at acetone concentrations < 1000 ppm shows that perception of odor intensity, information bias, and exposure history (i.e., habituation) are confounding factors in the reporting of irritation thresholds and health symptoms. In conclusion, subjective measures alone are inappropriate for establishing sensory irritation effects and sensory irritation threshold levels of odorants such as acetone. Clearly, the sensory irritation threshold of acetone should be based on objective measurements.
Asunto(s)
Acetona/efectos adversos , Irritantes/efectos adversos , Exposición Profesional/efectos adversos , Olfato/efectos de los fármacos , Adolescente , Adulto , Anciano , Animales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Odorantes , Umbral Sensorial/efectos de los fármacosRESUMEN
This report compares cancer classification systems, health risk assessment approaches, and procedures used for establishing occupational exposure limits (OELs), in various European countries and scientific organizations. The objectives were to highlight and compare key aspects of these processes and to identify the basis for differences in cancer classifications and OELs between various scientific organizations and countries. Differences in cancer classification exist in part due to differences in the ultimate purpose of classification and to the relative importance of different types of data (i.e., animal vs human data, mechanistic data, and data from benign vs malignant tumors). In general, the groups surveyed tend to agree on classification of chemicals with good evidence of carcinogenicity in humans, and agree less on classification of chemicals with positive evidence in animals and inadequate or limited evidence in humans. Most entities surveyed distinguish between genotoxic and nongenotoxic chemicals when conducting risk assessments. Although the risk assessment approach used for nongenotoxic chemicals is fairly similar among groups, risk assessment approaches for genotoxic carcinogens vary widely. In addition to risk assessment approaches, other factors which can affect OELs include selection of the critical effect, use of health-based vs technology-based exposure limits, and consideration of technological feasibility and socioeconomic factors.
Asunto(s)
Indicadores de Salud , Animales , Carcinógenos/clasificación , Carcinógenos/toxicidad , Europa (Continente) , Humanos , Exposición Profesional/normasRESUMEN
Humans are exposed to mixtures of chemicals, rather than to individual chemicals. From a public health point of view, it is most relevant to answer the question of whether or not the components in a mixture interact in a way that results in an increase in their overall effect compared with the sum of the effects of the individual components. In this article, options for the hazard identification and risk assessment of simple and complex chemical mixtures will be discussed. In addition, key research needed to continue the development of hazard characterization of chemical mixtures will be described. Clearly, more collaboration among toxicologists, model developers and pharmacologists will be necessary.
Asunto(s)
Sustancias Peligrosas/toxicidad , Modelos Químicos , Animales , Humanos , Medición de Riesgo , Pruebas de ToxicidadRESUMEN
Two independent bioassays are available which have examined the potential carcinogenicity of monomeric and polymeric methylene diphenyl diisocyanate (MDI) following long-term inhalation exposure in rats. These studies are not directly comparable, however, due to differences in design and conduct of the in-life phase, and differences in nomenclature used for some of the histopathological findings. This paper presents a definitive overview ofthe pulmonary toxicity of MDI developed following a thorough review of both investigations. As part of this process, the test materials and the designs of the studies were compared, and an in-depth review of lung lesions was conducted by an independent reviewing pathologist. This included the re-examination of the original lung slides, supported by an analysis of the exposure regimens, the results of which were used to develop an accurate profile of the doses received by the animals in the two studies. Histopathological findings were then combined with this information to give an overall dose-response curve for both studies as a whole. The range of total inhalation exposures to MDI was calculated as 559, 1972, 2881, 6001, 17,575 and 17,728 mgh/m3. Major pulmonary effects included increased lung weights together with bronchiolo-alveolar adenomas and hyperplasia, and interstitial fibrosis which occurred consistently in both studies, indicating a very similar qualitative response of the lungs to polymeric and monomeric MDI. The quantitative response of the lung was clearly dose-related in each study, and when the studies were considered as a whole a reasonable overall dose-response relationship was apparent for major lung lesions. Lung tumours (in low incidences) only occurred at the highest dose level in both studies (17,575 and 17,728 mgh/m3). For inflammatory and other non-neoplastic pulmonary changes, the lowest dose examined (559 mgh/m3) was regarded as a no-observed-adverse-effect-level for both polymeric and monomeric MDI. It was concluded that the results of the two studies could be combined to serve as a basis for human risk assessment of MDI.