RESUMEN
The unexpected finding of N-nitrosamine (NA) impurities in many pharmaceutical products raised significant challenges for industry and regulators. In addition to well-studied small molecular weight NAs, many of which are potent rodent carcinogens, novel NAs associated with active pharmaceutical ingredients have been found, many of which have limited or no safety data. A tiered approach to establishing Acceptable Intake (AI) limits for NA impurities has been established using chemical-specific data, read-across, or a class-specific TTC limit. There are â¼140 NAs with some rodent carcinogenicity data, but much of it is older and does not meet current guidelines for what constitutes a 'robust' bioassay. Nevertheless, these data are an important source of information to ensure the best science is used for assessing NA impurities and assuring consumer safety while minimizing impact that can lead to drug shortages. We present several strategies to maximize the use of imperfect data including using a lower confidence limit on a rodent TD50, and leveraging data from multiple NAs. Information on the chemical structure known to impact potency can also support development of an AI or potentially conclude that a particular NA does not fall in the cohort of concern for potent carcinogenicity.
Asunto(s)
Mutágenos , Nitrosaminas , Mutágenos/toxicidad , Mutágenos/química , Contaminación de Medicamentos , Medición de Riesgo , Carcinógenos/toxicidad , Carcinógenos/química , Preparaciones FarmacéuticasRESUMEN
Hydrogen peroxide has a long history of safe use in a wide variety of medical and consumer products, including oral care products. The use of hydrogen peroxide in tooth bleaching has been extended to home use. Because this represents a new use, questions have been raised regarding safety, particularly the potential for peroxide tooth-whitening products to increase the risk of oral cancer in high-risk individuals (e.g., smokers and drinkers). These concerns are based on limited experimental data in animals that hydrogen peroxide has extremely weak tumor promoting activity and a lack of publicly available data on exposure to peroxides from the home use of tooth-whitening products. This paper provides a weight-of-evidence cancer hazard characterization for hydrogen peroxide and presents a quantitative risk assessment that confirms a favorable human safety profile risk associated with low levels of exposure to hydrogen peroxide from the use of tooth-whitening products. This includes a lack of tumor promotion risk which is important because tooth-whitening products are often used by chronic smokers and drinkers, who may represent a susceptible subpopulation because of their exposure to other known carcinogens.
Asunto(s)
Peróxido de Hidrógeno/toxicidad , Oxidantes/toxicidad , Blanqueamiento de Dientes/efectos adversos , Consumo de Bebidas Alcohólicas , Animales , Carcinógenos , Seguridad de Productos para el Consumidor , Exposición a Riesgos Ambientales , Humanos , Metaanálisis como Asunto , Neoplasias de la Boca/epidemiología , Neoplasias de la Boca/etiología , Medición de Riesgo , Factores de Riesgo , FumarRESUMEN
Coumarin (1,2-benzopyrone) is a naturally occurring fragrant compound found in a variety of plants and spices. Exposure to the general public is through the diet and from its use as a perfume raw material in personal care products. High doses of coumarin by the oral route are known to be associated with liver toxicity in rodents. Chronic oral bioassays conducted in the 1990s reported liver tumors in rats and mice and lung tumors in mice, raising concerns regarding the safety of coumarin. Since then, an extensive body of research has focused on understanding the etiology of these tumors. The data support a conclusion that coumarin is not DNA-reactive and that the induction of tumors at high doses in rodents is attributed to cytotoxicity and regenerative hyperplasia. The species-specific target organ toxicity is shown to be related to the pharmacokinetics of coumarin metabolism, with data showing rats to be particularly susceptible to liver effects and mice to be particularly susceptible to lung effects. A quantitative human health risk assessment that integrates both cancer and non-cancer effects is presented, confirming the safety of coumarin exposure from natural dietary sources as well as from its use as a perfume in personal care products.
Asunto(s)
Anticoagulantes/toxicidad , Cumarinas/toxicidad , Animales , Perros , Exposición a Riesgos Ambientales , Humanos , Ratones , Primates , Ratas , Medición de Riesgo , Especificidad de la Especie , Pruebas de ToxicidadRESUMEN
Conducting a sound skin sensitization risk assessment prior to the introduction of new ingredients and products into the market place is essential. The process by which low-molecular-weight chemicals induce and elicit skin sensitization is dependent on many factors, including the ability of the chemical to penetrate the skin, react with protein, and trigger a cell-mediated immune response. Based on our chemical, cellular and molecular understanding of allergic contact dermatitis, it is possible to carry out a quantitative risk assessment. Specifically, by estimating the exposure to the allergen and its allergenic potency, it is feasible to assess quantitatively the sensitization risk of an ingredient in a particular product type. This paper focuses on applying exposure-based risk assessment tools to understanding fragrance allergy for 2 hypothetical products containing the fragrance allergen cinnamic aldehyde. The risk assessment process predicts that an eau de toilette leave-on product containing 1000 ppm or more cinnamic aldehyde would pose an unacceptable risk of induction of skin sensitization, while a shampoo, containing the same level of cinnamic aldehyde, would pose an acceptable risk of induction of skin sensitization, based on limited exposure to the ingredient from a rinse-off product application.
Asunto(s)
Acroleína/análogos & derivados , Acroleína/efectos adversos , Alérgenos/efectos adversos , Dermatitis Alérgica por Contacto/prevención & control , Preparaciones para el Cabello/efectos adversos , Perfumes/efectos adversos , Medición de Riesgo/métodos , Acroleína/administración & dosificación , Alérgenos/administración & dosificación , Animales , Seguridad de Productos para el Consumidor , Dermatitis Alérgica por Contacto/etiología , Cobayas , Humanos , Perfumes/administración & dosificación , Factores de TiempoRESUMEN
The ultimate goal of the research reported in this series of three articles is to derive distributions of doses of selected environmental tobacco smoke (ETS)-related chemicals for nonsmoking workers. This analysis uses data from the 16-City Study collected with personal monitors over the course of one workday in workplaces where smoking occurred. In this article, we describe distributions of ETS chemical concentrations and the characteristics of those distributions (e.g., whether the distribution was log normal for a given constituent) for the workplace exposure. Next, we present population parameters relevant for estimating dose distributions and the methods used for estimating those dose distributions. Finally, we derive distributions of doses of selected ETS-related constituents obtained in the workplace for people in smoking work environments. Estimating dose distributions provided information beyond the usual point estimate of dose and showed that the preponderance of individuals exposed to ETS in the workplace were exposed at the low end of the dose distribution curve. The results of this analysis include estimations of hourly maxima and time-weighted average (TWA) doses of nicotine from workplace exposures to ETS (extrapolated from 1 day to 1 week) and doses derived from modeled lung burdens of ultraviolet-absorbing particulate matter (UVPM) and solanesol resulting from workplace exposures to ETS (extrapolated from 1 day to 1 year).
Asunto(s)
Contaminantes Ocupacionales del Aire/análisis , Contaminantes Atmosféricos/análisis , Exposición a Riesgos Ambientales/análisis , Exposición Profesional/análisis , Contaminación por Humo de Tabaco/análisis , Absorción , Adulto , Algoritmos , Alcaloides/análisis , Femenino , Humanos , Modelos Lineales , Pulmón/metabolismo , Masculino , Modelos Biológicos , Nicotina/análisis , Agonistas Nicotínicos/análisis , Probabilidad , Piridinas/análisis , Escopoletina/análisis , Factores Sexuales , Fumar , Terpenos/análisis , Factores de Tiempo , Rayos Ultravioleta , Lugar de TrabajoRESUMEN
Estimating gastrointestinal absorption remains a significant challenge in the risk assessment of metals. This presentation reviews our current understanding of the gastrointestinal absorption of lead (Pb) to illustrate physiological mechanisms involved in metal absorption, new approaches that are being applied to the problem of estimating metal absorption in humans, and issues related to integrating this information into risk assessment. Absorption of metals can be highly variable in human populations because it is influenced by a variety of factors that include the chemical form of the metal, environmental matrix in which the ingested metal is contained, gastrointestinal tract contents, diet, nutritional status, age, and, in some cases, genotype. Thus, in risk assessment models, gastrointestinal absorption is best described as a variable whose distribution is determined in part by the above multiple influences. Although we cannot expect to evaluate empirically each of the above factors in human populations, we can expect to achieve a sufficiently detailed understanding of absorption mechanisms to develop conceptual and, eventually, quantitative models of absorption that account for some aspects of individual variability. A conceptual model is presented of the physiological processes involved in the transfer of ingested metals from the lumen of the gastrointestinal tract to the blood circulation. Components of the model include delivery to the site(s) of absorption; distribution among intracellular and extracellular ligands and transcellular and paracellular pathways of transfer across the gastrointestinal tract epithelium. The gastrointestinal absorption of Pb is discussed in the context of this model.
Asunto(s)
Sistema Digestivo/metabolismo , Metales Pesados/metabolismo , Animales , Disponibilidad Biológica , Cadmio/metabolismo , Humanos , Absorción Intestinal , Plomo/sangre , Plomo/metabolismo , Manganeso/metabolismo , Metales Pesados/sangre , Metales Pesados/farmacocinética , Modelos Biológicos , Níquel/metabolismo , Medición de RiesgoRESUMEN
Risk assessment involves establishing scientifically defensible dose-response relationships for end points of concern. For Cr(VI)-contaminated soils, this includes conducting dose-response assessments for blood, liver, and kidney toxicity following oral exposure; lung cancer following inhalation exposure; and allergic contact dermatitis following dermal exposure. This dose-response information is then integrated with a site-specific exposure assessment (or default assumptions) in order to develop a site-specific (or generic) soil criterion within the framework of a comprehensive risk characterization. Risk managers develop cleanup standards designed to protect against all possible adverse effects, taking into account these site-specific (or generic) criteria and other factors such as technical feasibility, cost-benefit analyses, and socio-political concerns. Recently a push for cost-benefit analyses of environmental decisions has occurred, further supporting the need for risk assessors to prepare a comprehensive risk characterization, with its attendant uncertainties. These risk assessment and management issues are brought to the forefront by risk assessors and risk managers dealing with Cr(VI)-contaminated soils. This article offers a review and analysis of the risk characterization of Cr(VI)-contaminated soils, showing that the differing toxicities with route of exposures do not necessarily lead to different characterizations or risk. Soil concentrations in the range of 130 to 450 ppm appear to protect against noncancer toxicity from oral exposure, cancer toxicity from inhalation exposure, and allergic contact dermatitis from dermal exposure.
Asunto(s)
Compuestos de Cromo/toxicidad , Medición de Riesgo , Contaminantes del Suelo/toxicidad , Administración por Inhalación , Administración Oral , Administración Tópica , Compuestos de Cromo/administración & dosificación , Dermatitis por Contacto/epidemiología , Relación Dosis-Respuesta a Droga , Polvo , Humanos , Concentración de Iones de Hidrógeno , Tamaño de la Partícula , Estados Unidos , United States Environmental Protection AgencyRESUMEN
MTBE is a volatile organic compound used as an oxygenating agent in gasoline. Inhalation from fumes while refueling automobiles is the principle route of exposure for humans, and toxicity by this route has been well studied. Oral exposures to MTBE exist as well, primarily due to groundwater contamination from leaking stationary sources, such as underground storage tanks. Assessing the potential public health impacts of oral exposures to MTBE is problematic because drinking water studies do not exist for MTBE, and the few oil-gavage studies from which a risk assessment could be derived are limited. This paper evaluates the suitability of the MTBE database for conducting an inhalation route-to-oral route extrapolation of toxicity. This includes evaluating the similarity of critical effect between these two routes, quantifiable differences in absorption, distribution, metabolism, and excretion, and sufficiency of toxicity data by the inhalation route. We conclude that such an extrapolation is appropriate and have validated the extrapolation by finding comparable toxicity between a subchronic gavage oral bioassay and oral doses we extrapolate from a subchronic inhalation bioassay. Our results are extended to the 2-year inhalation toxicity study by Chun et al. (1992) in which rats were exposed to 0, 400, 3000, or 8000 ppm MTBE for 6 hr/d, 5 d/wk. We have estimated the equivalent oral doses to be 0, 130, 940, or 2700 mg/kg/d. These equivalent doses may be useful in conducting noncancer and cancer risk assessments.
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Carcinógenos/toxicidad , Éteres Metílicos/toxicidad , Solventes/toxicidad , Absorción , Contaminantes Atmosféricos/metabolismo , Contaminantes Atmosféricos/farmacocinética , Contaminantes Atmosféricos/orina , Animales , Automóviles , Carcinógenos/metabolismo , Carcinógenos/farmacocinética , Bases de Datos como Asunto , Exposición a Riesgos Ambientales , Femenino , Gasolina , Humanos , Masculino , Éteres Metílicos/metabolismo , Éteres Metílicos/farmacocinética , Éteres Metílicos/orina , Neoplasias Experimentales/inducido químicamente , Probabilidad , Salud Pública , Ratas , Reproducibilidad de los Resultados , Medición de Riesgo , Solventes/metabolismo , Solventes/farmacocinética , Contaminantes Químicos del Agua/toxicidad , Abastecimiento de AguaRESUMEN
Estimating gastrointestinal absorption remains a significant challenge in the risk assessment of metals. This presentation reviews our current understanding of the gastrointestinal absorption of lead (Pb) to illustrate physiological mechanisms involved in metal absorption, new approaches that are being applied to the problem of estimating metal absorption in humans, and issues related to integrating this information into risk assessment. Absorption of metals can be highly variable in human populations because it is influenced by a variety of factors that include the chemical form of the metal, environmental matrix in which the ingested metal is contained, gastrointestinal tract contents, diet, nutritional status, age, and, in some cases, genotype. Thus, in risk assessment models, gastrointestinal absorption is best described as a variable whose distribution is determined in part by the above multiple influences. Although we cannot expect to evaluate empirically each of the above factors in human populations, we can expect to achieve a sufficiently detailed understanding of absorption mechanisms to develop conceptual and, eventually, quantitative models of absorption that account for some aspects of individual variability. A conceptual model is presented of the physiological processes involved in the transfer of ingested metals from the lumen of the gastrointestinal tract to the blood circulation. Components of the model include delivery of the metal to the site(s) of absorption; distribution of metal among intracellular and extracellular ligands and transcellular and paracellular pathways of transfer across the gastrointestinal tract epithelium. The gastrointestinal absorption of Pb is discussed in the context of this model.
Asunto(s)
Sistema Digestivo/metabolismo , Metales Pesados/metabolismo , Disponibilidad Biológica , Cadmio/metabolismo , Humanos , Absorción Intestinal , Mucosa Intestinal/metabolismo , Plomo/metabolismo , Manganeso/metabolismo , Metales Pesados/sangre , Metales Pesados/farmacocinética , Níquel/metabolismo , Medición de RiesgoRESUMEN
Acrylonitrile (ACN) is a monomer used extensively in the production of plastics, synthetic fibers, and rubber. In previous assessments conducted by IARC and the EPA, ACN was classified as a probable human carcinogen based on limited evidence in humans and sufficient evidence in laboratory animals. Specifically, EPA had determined that there was an association between ACN exposure and lung cancer based on a study by O'Berg (1980, J. Occup. Med. 22, 245-252). However, a follow-up of this cohort (O'Berg et al., 1985, J. Occup. Med. 27, 835-840) shows no statistically significant excess of lung cancer mortality or incidence. Our evaluation of the more recent human database taken as a whole shows that there is not a clear association between ACN exposure and human cancer, yet the studies have insufficient power to be able to rule out a small increase. In laboratory rats, however, ACN has been shown to be clearly carcinogenic by the oral and inhalation routes. Applying the methodology of EPA's proposed 1996 cancer risk assessment guidelines to the rat tumor data, the estimated upper bound on the excess lifetime risk at continuous exposure to 1 microgram/m3 ACN is calculated to be in the range of 8.2 x 10(-6) to 1.1 x 10(-5).
Asunto(s)
Acrilonitrilo/toxicidad , Carcinógenos/toxicidad , Neoplasias/inducido químicamente , Enfermedades Profesionales/inducido químicamente , Exposición Profesional , Administración por Inhalación , Animales , Estudios de Cohortes , Bases de Datos Bibliográficas , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Neoplasias/epidemiología , Enfermedades Profesionales/patología , Ratas , Ratas Endogámicas , Medición de RiesgoRESUMEN
The science behind the use of uncertainty factors has progressed considerably. Increased knowledge of inter- and intraspecies sensitivity, mechanisms of action, and detailed evaluation of data bases can support the use of data-derived uncertainty factors, which ultimately results in a risk assessment with greater confidence. Papers that highlight available data for each of several areas of uncertainty are discussed, indicating that choice of the appropriate factor requires scientific judgement on a case-by-case basis. Case studies from EPA and Health Canada risk values illustrate the use of data in chemical specific risk assessments to support the selection of uncertainty factors other than the default value of 10-fold. In the case studies, the types of data that have been used to support a change in the default value are explicitly reviewed, as well as why the data support a different uncertainty factor, how the uncertainty was reduced, and what assumptions have been satisfied or replaced. Incorporation of all available scientific data into the risk assessment process fosters increased research and ultimately reduces uncertainty. The results of this review support the use of data-derived uncertainty factors when appropriate scientific data are available.