RESUMEN
A workshop entitled "Implementation of EPA Revised Cancer Assessment Guidelines: Incorporation of Mechanistic and Pharmacokinetic Data" was held in Anaheim, California, in 1996 at the 35th Annual Meeting of the Society of Toxicology (SOT). This workshop was jointly sponsored by the Carcinogenesis, Risk Assessment, and Veterinary Specialty Sections of the SOT. The thrust of the workshop was to discuss the scientific basis for the revisions to the EPA Guidelines for cancer assessment and EPA's plans for their implementation. This is the first revision to the original EPA guidelines which have been in use by EPA since 1986. The principal revisions are intended to provide a framework for an increased ability to incorporate biological data into the risk assessment process. Two cases were presented, for chloroform and triclioroethylene, that demonstrated the use of the revised guidelines for specific cancer risk assessments. Using these new guidelines, nonlinear margin of exposure analyses were proposed for these chemicals instead of the linearized multistage model previously used by the EPA as the default method. The workshop participants generally applauded the planned revisions to the EPA guidelines. For the most part, they considered that the revised guidelines represented a positive step which should allow for and encourage the use of biological information in the conduct of cancer risk assessments. Several participants cautioned however that the major problem with cancer risk assessments would continue to be the inadequacy of available data on which to conduct more scientific risk assessments.
Asunto(s)
Carcinógenos/efectos adversos , Exposición a Riesgos Ambientales/efectos adversos , Guías como Asunto , Neoplasias/etiología , Animales , Cloroformo/efectos adversos , Humanos , Modelos Estadísticos , Medición de Riesgo , Tricloroetileno/efectos adversos , Estados Unidos , United States Environmental Protection AgencyRESUMEN
Adult male and female Sprague-Dawley rats received epichlorohydrin via gavage in distilled water for 10 consecutive days at dose levels of 3, 7, 19, and 46 mg/kg-day, and for 90 days at dose levels of 1, 5, and 25 mg/kg-day. Epichlorohydrin did not adversely effect mortality, but toxicity, at the higher doses, was evident by: 1) losses in body weight gain and organ weights, 2) reductions in food and water consumption, and 3) in the hematological and microscopic examinations in both study periods. Significant decreases in erythrocyte count, hemoglobin, and hematocrit levels were found in the high dose level in males after 10 and 90 days. Dose-related increases in kidney and liver weights were observed in both sexes at 25 mg/kg-day in the 90-day study and in various organs for both 19 and 46 mg/kg-day in the 10-day study. Histopathological examination identified the forestomach as the primary target organ for both sexes and in both studies with significant dose-related increases in mucosal hyperplasia (acanthosis) and hyperkeratosis. Based on the data presented, a lowest observable adverse effect level (LOAEL) for oral exposure of Sprague-Dawley rats to epichlorohydrin is 3 mg/kg-day for 10 days and 1 mg/kg-day is suggested as the no observed adverse effect level (NOAEL) for a 90 day oral exposure. These conclusions were the same whether the lesions were analyzed for each sex individually or whether the data in each study was pooled.
Asunto(s)
Carcinógenos/toxicidad , Epiclorhidrina/toxicidad , Solventes/toxicidad , Estómago/efectos de los fármacos , Administración Oral , Alimentación Animal , Animales , Análisis Químico de la Sangre , Carcinógenos/administración & dosificación , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/efectos de los fármacos , Epiclorhidrina/administración & dosificación , Femenino , Riñón/efectos de los fármacos , Riñón/crecimiento & desarrollo , Hígado/efectos de los fármacos , Hígado/crecimiento & desarrollo , Masculino , Nivel sin Efectos Adversos Observados , Tamaño de los Órganos/efectos de los fármacos , Ovario/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Caracteres Sexuales , Solventes/administración & dosificación , Estómago/anomalías , Testículo/efectos de los fármacos , Testículo/crecimiento & desarrollo , Factores de Tiempo , Aumento de Peso/efectos de los fármacosRESUMEN
1,1,1-Trichloro-2-propanone (1,1,1-TCP) has been identified as a chlorination by-product in finished drinking water supplies. Since little was known of its oral toxicity, exposure studies were conducted with male and female Sprague-Dawley rats (10 males and 10 females/group) exposed by corn oil gavage at 0, 16, 48, 161, or 483 mg/kg for 10 d or 0, 30, 90, or 270 mg/kg for 90 d. Evaluations included mortality, clinical signs, body weight, food consumption, ophthalmology, hematology, clinical chemistry, urinalysis, organ weights, gross pathology, and histopathology. In the 10-d study, severe toxicity was observed at the highest dose level, since most treated animals (8/10 males and 7/10 females) died. Toxicity was also noted at 161 and 48 mg/kg. At 161 mg/kg, 2 males died and an increase in liver weights in both sexes was observed. Acanthosis and hyperkeratosis of the forestomach was present in males and females at 48 mg/kg and above. In the 90-d study, toxicity was significant at 270 mg/kg, with acanthosis and hyperkeratosis of the forestomach evident in most animals and ataxia in about one-half of them. Retinal degeneration, increased serum potassium, and increased blood urea nitrogen were present in females and increased blood calcium in males at that same dose level. Acanthosis and hyperkeratosis were observed in both sexes, and retinal degeneration was prominent in 2 females at 90 mg/kg. It was concluded that 16 mg/kg was the NOAEL (no observed adverse effect level) for the 10-d study while 30 mg/kg was the NOAEL for the 90-d exposure of Sprague-Dawley rats to 1,1,1,-trichloro-2-propanone.
Asunto(s)
Acetona/análogos & derivados , Mutágenos/toxicidad , Estómago/efectos de los fármacos , Acetona/administración & dosificación , Acetona/toxicidad , Administración Oral , Animales , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Femenino , Masculino , Mutágenos/administración & dosificación , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Estómago/patologíaRESUMEN
1,3-Dichloropropanone (1,3-DCP) has been identified as a by-product of the chlorination of water and thus a potential contaminant in drinking water. Since little was known of its oral toxicity, subchronic exposure studies were conducted with male and female Sprague-Dawley rats exposed to 1,3-DCP in drinking water at 0, 5, 65, or 125 ppm for 90 days. Evaluations included mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, organ weights, gross pathology, and histopathology. No significant organ toxicity was detected although an aversion to drinking 1,3-DCP treated water was observed at 65 and 125 ppm. The only consistent change was a decrease in BUN at 125 ppm in both sexes. Based on a decrease in BUN levels and decreased water consumption, 5 ppm (0.5 mg/kg/day) was considered the NOAEL.
Asunto(s)
Acetona/análogos & derivados , Acetona/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Leucocitos/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Groups of 10 male and 10 female Sprague-Dawley rats were administered 1,1-dichloro-2-propanone in corn oil by gavage at 0, 10, 20, 40, or 80 mg/kg/day for 90 consecutive days. Food and water consumption, body and organ weights, organ-to-body weight ratios, hematology, and clinical chemistry parameters were determined. Gross and microscopic pathology examinations also were conducted. No treatment-related mortality was observed during the study; however, liver, forestomach, and kidney toxicity was evident. Liver changes consisted of cytoplasmic alteration, cytomegaly, karyomegaly, and bile duct hyperplasia. These occurred with significance of p < or = 0.05 at or above 10 mg/kg/day in both sexes. The forestomach lesions included hyperkeratosis and epithelial hyperplasia in both sexes at 40 and 80 mg/kg/day, and ulcerations at 80 mg/kg/day. Also, an increased incidence and severity of spontaneously occurring chronic progressive nephropathy was most apparent in high dose males. Increases in organ-to-body weight ratios were noted for the liver and kidneys in females at the highest dose level and in males at the two highest dose levels. Serum enzymes (ALT, AST, and LDH) were increased in females and decreased in males. Based on liver lesions and biochemical changes, it was concluded that there was no experimentally definable NOAEL.
Asunto(s)
Acetona/análogos & derivados , Acetona/toxicidad , Administración Oral , Animales , Peso Corporal/efectos de los fármacos , Aceite de Maíz , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Riñón/efectos de los fármacos , Riñón/patología , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Estómago/efectos de los fármacos , Estómago/patología , Factores de TiempoRESUMEN
The chlorinated acetaldehydes, chloral hydrate (CH) and 2-chloroacetaldehyde (CAA), have been identified as chlorination by-products in finished drinking water supplies. Although both chemicals are genotoxic, their potential for carcinogenicity had not been adequately explored. The studies reported here are chronic bioassays conducted with male B6C3F1 mice exposed to levels of 1 g/liter CH and 0.1 g/liter CAA via the drinking water for 104 weeks. Distilled water (H2O) served as the untreated control and dichloroacetic acid (DCA; 0.5 g/liter), another chlorine disinfection by-product, was included. The mean daily ingested doses were approximately 166 mg/kg/day for CH, 17 mg/kg/day for CAA, and 93 mg/kg/day for DCA. Evaluations included mortality, body weight, organ weights, gross pathology, and histopathology. The primary target organ was the liver as the organ weights and pathological changes in the other organs (spleen, kidneys, and testes) were comparable between the treated groups and the H2O control group. Liver weights were increased for all three test chemicals at the terminal euthanasia with the greatest increase seen in the CH and DCA groups. Hepatocellular necrosis was induced by all three test chemicals, and it was also most prevalent and severe in the CH and DCA groups. A significant increase in the prevalence of liver tumors was seen for all three chemicals. The strongest response was with DCA, in which 63% of the 104-week survivors had hepatocellular carcinomas (carcinomas) and 42% possessed hepatocellular adenomas (adenomas) and the combined prevalence for carcinomas plus adenoma was 75%. The corresponding prevalence rate for carcinomas, adenomas, and combined tumors were 46, 29, and 71%; 31, 8, and 38%; and 10, 5, and 15% for CH, CAA, and H2O, respectively. In addition to the tumors we evaluated the prevalence of a possible preneoplastic lesion, the hepatocellular hyperplastic nodule (nodules), a lesion which occurred in all three treated groups but not in the H2O group.
Asunto(s)
Acetaldehído/análogos & derivados , Carcinógenos/toxicidad , Hidrato de Cloral/toxicidad , Ácido Dicloroacético/toxicidad , Neoplasias Hepáticas Experimentales/inducido químicamente , Acetaldehído/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Conducta de Ingestión de Líquido/efectos de los fármacos , Femenino , Riñón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Tamaño de los Órganos/efectos de los fármacos , Bazo/patología , Testículo/patologíaRESUMEN
Male and female Sprague-Dawley rats were administered drinking water containing 300, 600, 1200, or 2400 mg/L chloral hydrate for 90 days. A control group received distilled water only. No animals died during the study and no differences were observed in body weight gain or food and water consumption, except for males at the highest-dose level. Minor treatment-related effects were observed for organ weights and hematological parameters and these did not appear to be of toxicological significance. Some indications of toxicity were evident in the 2400 mg/L male group (equivalent to 168 mg/kg-day) including a significant decrease in food and water consumption and in weight gain. In addition, histopathological examination of these animals revealed an apparent increase in the incidence of focal hepatocellular necrosis. Increases in AST, ALT, and LDH, which occurred at several dose levels in males, but particularly at 200 mg/L, are consistent with the hepatocellular necrosis of minimal to mild severity diagnosed by microscopic examination. These liver changes, except for sporadic enzyme changes, were not seen in the female rats which actually consumed higher doses of chloral hydrate (e.g., 288 mg/kg-day at 2400 mg/L). On the basis of the mild liver toxicity (histopathological and clinical) observed in males at the highest doses (168 mg/kg-day), the no observed adverse effect level (NOAEL) for oral exposure of rats to chloral hydrate for 90 days is considered to be 96 mg/kg-day (600 mg/L).
Asunto(s)
Hidrato de Cloral/toxicidad , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Conducta Animal/efectos de los fármacos , Nitrógeno de la Urea Sanguínea , Peso Corporal/efectos de los fármacos , Calcio/sangre , Creatinina/sangre , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Índices de Eritrocitos/efectos de los fármacos , Femenino , L-Lactato Deshidrogenasa/sangre , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Necrosis , Tamaño de los Órganos/efectos de los fármacos , Fosfatos/sangre , Ratas , Ratas Sprague-DawleyRESUMEN
Male and female Sprague-Dawley rats were administered the sodium salt of monochloroacetic acid (SMCA) by oral gavage for a period of 90 consecutive days. Dosage levels of 15, 30, 60 or 120 mg/kg per day were employed. SMCA clearly induced toxicity in both females and males, with the greatest severity in the male animals. Both the liver and kidneys were identified as target organs. At 120 mg/kg per day, 30% of females and 80% of the males died, most within the first 2 days of treatment. Hemorrhagic and congested lungs (possibly a postmortem change) were seen in the early deaths (1-3 days) whereas liver lesions were observed in later deaths. In addition, there was nephrotoxicity as evidenced by elevated creatinine, blood calcium (BCAL), and blood urea nitrogen (BUN) levels. Hepatotoxicity was indicated by increases in the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Both organs showed increased organ-to-body weight ratios. Microscopic examination revealed a significant (P less than or equal to 0.001) increase in chronic renal nephropathy and increased splenic pigmentation at 60 mg/kg per day in the males. Based on the observation of toxicity at all treatment levels in males, a lowest observed adverse effect level (LOAEL) of 15 mg/kg per day is proposed for a 90-day exposure to SMCA by oral gavage to the Sprague--Dawley rat.
Asunto(s)
Acetatos/toxicidad , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Nitrógeno de la Urea Sanguínea , Peso Corporal/efectos de los fármacos , Calcio/sangre , Creatinina/sangre , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Corazón/efectos de los fármacos , Pulmón/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas , Caracteres Sexuales , Bazo/efectos de los fármacosRESUMEN
The concern from low-level exposure to acrylonitrile is primarily due to its potential for carcinogenicity. Several epidemiology studies provide suggestive evidence for an association of lung cancer in workers exposed to acrylonitrile; however, smoking may be a contributing factor and therefore the role of acrylonitrile as a causative factor is unclear. Seven animal bioassays, using three routes of exposure and two strains of rats, have provided consistent results. Tumors were induced in all studies, with the primary sites of tumor induction being the brain, ear canal, gastrointestinal tract and mammary glands. The linearized multistage model was used for extrapolation purposes. The risk based on brain tumors (astrocytomas) and stomach tumors following oral exposures ranged from 1 x 10(-1) to 4 x 10(-1)mg-1kg-1day-1. The risk of inhalation exposure is somewhat less, (2-3) x 10(-2). Support for carcinogenic potential is obtained from mutagenicity studies. Acrylonitrile has been found to be mutagenic and also binds with DNA. It has been speculated that acrylonitrile is metabolized to 2-cyanoethylene oxide, which is the proximate carcinogen.
Asunto(s)
Acrilonitrilo/toxicidad , Carcinógenos , Exposición a Riesgos Ambientales , Acrilonitrilo/metabolismo , Animales , Pruebas de Carcinogenicidad , Femenino , Humanos , Masculino , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/patología , Ratas , Ratas Endogámicas , Factores de RiesgoRESUMEN
Liquid gasoline is a complex mixture of at least 150 hydrocarbons with about 60-70% alkanes (paraffins), 25-30% aromatics, and 6-9% alkenes. In order to evaluate the potential for health effects from inhaling gasoline vapors, it is essential to understand the major differences in the composition of vapors versus liquid gasoline. The small chain, low carbon-numbered components are more volatile and thus in higher percentages in the vapor phase than the larger and heavier molecules. It is noteworthy that the concentrations of aromatics (the more toxic of the gasoline components), are depleted to about 2% in the vapor phase, with the light paraffins (the less toxic) enriched to about 90%. Actual measurements of vapor exposure at service stations confirm that the vapor composition is primarily to low weight alkanes although benzene is also emitted and represents the chemical of greatest concern. A perceived health concern from inhaling gasoline vapors is the potential for carcinogenicity based on the induction of kidney tumors in male rats and liver tumors in female mice exposed to wholly-vaporized gasoline. However, the results of the animal studies are of questionable relevance for human risk assessment due to the unique mechanism operative only in the male rat and since the exposure was to wholly-vaporized gasoline rather than the gasoline vapor mixture to which humans are exposed. Recent research supports the hypothesis that branched-chain-alkanes bind to a globulin specific to make rats, alpha 2-u-globulin. The protein complex can not be degraded in the usual manner so that protein accumulation occurs in renal cells, leading to cytotoxicity, death, proliferation, and with prolonged exposure, kidney cancer. The results of epidemiology studies fail to link an increase in cancer to exposure to gasoline vapors.
Asunto(s)
Contaminantes Atmosféricos/efectos adversos , Gasolina/efectos adversos , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/toxicidad , Animales , Gasolina/análisis , Humanos , Petróleo , Riesgo , Estados Unidos , United States Environmental Protection Agency , VolatilizaciónRESUMEN
For the foreseeable future toxicologists will continue to rely on animal bioassays as the main predictive tools for safety evaluation. While their predictive value is good, there are serious limitations which must be recognized in applying the test results to assess human risk. These limitations are of especially great concern for chronic toxicity tests. During the past decade numerous protocols and guidelines for chronic toxicity and carcinogenesis tests have been developed by national and international organizations. These have been reviewed with two aspects in mind: the potential for standardization and the assessment of issues of greatest concern. Of the major design aspects, animal models, route of exposure, dose selection, pathology, and reporting requirements are the most controversial. While a degree of standardization of protocols has many advantages, complete standardization is not considered desirable as test objectives may differ, and overly rigid protocols would likely stifle development of improved methodology. One of the greatest dilemmas facing government health agencies is the extent of pathology to require in routine bioassays. A thorough microscopic examination is obviously desirable; however, the increased requirements for testing chemicals using the extensive pathology protocols now in existence has created a demand exceeding available scientific manpower.
Asunto(s)
Carcinógenos/toxicidad , Toxicología/métodos , Envejecimiento , Crianza de Animales Domésticos , Animales , Carcinógenos/administración & dosificación , Fenómenos Químicos , Química , Evaluación Preclínica de Medicamentos , Neoplasias Experimentales/patología , Factores de Tiempo , Toxicología/normasRESUMEN
The long-term administration of 50 and 100 ppm of Mirex in the diets of male and female Charles River CD rats was associated with a spectrum of liver lesions, from foci or areas of cellular alteration and neoplastic nodules to hepatocellular carcinoma. Statistically significant numbers of neoplastic nodules were observed in the livers of male rats receiving the high dose. Neoplastic nodules and hepatocellular carcinomas were not observed in control rats.
Asunto(s)
Carcinógenos , Carcinoma Hepatocelular/inducido químicamente , Insecticidas/toxicidad , Neoplasias Hepáticas/inducido químicamente , Mírex/toxicidad , Animales , Neoplasias Encefálicas/inducido químicamente , Carcinoma Hepatocelular/patología , Enfermedad Hepática Inducida por Sustancias y Drogas , Femenino , Leucemia Experimental/inducido químicamente , Hepatopatías/patología , Neoplasias Hepáticas/patología , Linfoma/inducido químicamente , Masculino , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/patología , Neoplasias Hipofisarias/inducido químicamente , Ratas , Neoplasias Cutáneas/inducido químicamente , Neoplasias Urogenitales/inducido químicamenteRESUMEN
A carcinogenic in an animal bioassay is usually characterized by gradaul accumulation of a tumor incidence significantly in excess in the treated versus the control animals. In some cases, a definite response is realized relatively early, prior to planned sacrifice. In others, positive results are found at termination. In both cases, a long delay may occur before the information is ready to reach the public due to the time needed to complete pathology, data analysis, publication of a report. Since the finding that a chemical is carcinogenic may have serious implications for public health and technology, reports of carcinogenesis bioassays should be thoroughly and critically reviewed before being issued. A delicate ethical dilemma confronts scientists in selecting the proper timing and extent for the release of carcinogenesis test results. Early findings may not be confirmed and may cause technological and economic problems and unnecessary anxiety. On the other hand, delaying public notification of highly suspicious findings until a final, detailed report is published, may delay preventive actions that could protect exposed populations from unnecessary risks. To meet differing requirements in regard to timing and extent of reporting, procedures were developed to issue reports on National Cancer Institute (NCI) carcinogenesis bioassays when the findings are clearly identified and well documented in the following forms: a) reports of preliminary findings, when the evidence is strongly suggestive; b) summary reports of completed bioassays; and c) detailed technical reports. Availability of such reports, particularly for preliminary findings, will be announced in the Federal Register and in a press release. The reports will be submitted for publication in the scientific literature.