ABSTRACT
Quickly changing technologies and intensive uses of radiofrequency electromagnetic field (RF-EMF)emitting phones pose a challenge to public health. Mobile phone users and uses and exposures to other wireless transmitting devices (WTDs) have increased in the past few years. We consider that CERENAT, a French national study, provides an important addition to the literature evaluating the use of mobile phones and risk of brain tumors. The CERENAT finding of increased risk of glioma is consistent with studies that evaluated use of mobile phones for a decade or longer and corroborate those that have shown a risk of meningioma from mobile phone use. In CERENAT, exposure to RFEMF from digitally enhanced cordless telephones (DECTs), used by over half the population of France during the period of this study, was not evaluated. If exposures to DECT phones could have been taken into account, the risks of glioma from mobile phone use in CERENAT are likely to be higher than published. We conclude that radiofrequency fields should be classified as a Group 2A ÌprobableÌ human carcinogen under the criteria used by the International Agency for Research on Cancer (Lyon, France). Additional data should be gathered on exposures to mobile and cordless phones, other WTDs, mobile phone base stations and WiFi routers to evaluate their impact on public health. We advise that the as low as reasonable achievable (ALARA) principle be adopted for uses of this technology, while a major crossdisciplinary effort is generated to train researchers in bioelectromagnetics and provide monitoring of potential health impacts of RFEMF.
Subject(s)
Brain Neoplasms/etiology , Carcinogens/classification , Cell Phone , Electromagnetic Fields/adverse effects , Glioma/etiology , Brain Neoplasms/epidemiology , France/epidemiology , Glioma/epidemiology , Humans , Risk FactorsABSTRACT
Ginkgo biloba extract has been used primarily as a medicinal agent in the treatment or prevention of cardiovascular and cerebrovascular dysfunction. Ginkgo biloba extract was nominated for study by the National Cancer Institute because of its widespread use as an herbal supplement to promote mental function and the limited availability of toxicity and carcinogenicity data. Furthermore, one of the major ingredients in Ginkgo biloba extract, quercetin, is a known mutagen. The Ginkgo biloba extract used in the current studies was procured from a supplier known to provide material to United States companies and contained 31.2% flavonol glycosides, 15.4% terpene lactones (6.94% bilo-balide, 3.74% ginkgolide A, 1.62% ginkgolide B, 3.06% ginkgolide C), and 10.45 ppm ginkgolic acid. Male and female F344/N rats and B6C3F1/N mice were administered Ginkgo biloba extract in corn oil by gavage for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 62.5, 125, 250, 500, or 1,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. Additional groups of 10 male and 10 female rats (clinical pathology study) were administered the same doses, 5 days per week for 23 days. All rats survived to the end of the study. Mean body weights of all dosed groups were similar to those of the vehicle control groups. Liver weights of all dosed groups of males and females were significantly greater than those of the vehicle control groups. The incidences of hepatocyte hypertrophy in all dosed groups of males and in 500 and 1,000 mg/kg females were significantly greater than those in the vehicle control groups; there was a dose-related increase in severity of this lesion in males. Hepatocyte fatty change occurred in all dosed males. The incidences of thyroid gland follicular cell hypertrophy were significantly increased in 500 and 1,000 mg/kg males and in 1,000 mg/kg females. The incidences of pigmentation in the olfactory epithelium of the nose were significantly increased in 500 and 1,000 mg/kg males and in females administered 125 mg/kg or greater. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were administered 0, 125, 250, 500, 1,000, or 2,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. One female mouse in the 1,000 mg/kg group died of a dosing accident during week 11. Mean body weights of 2,000 mg/kg females were significantly less than those of the vehicle control group. Ruffled fur was observed in two 1,000 mg/kg males between weeks 7 and 8 and all 2,000 mg/kg males between weeks 5 and 9. Liver weights of 250 mg/kg or greater males and all dosed groups of females were significantly greater than those of the vehicle control groups. Kidney weights of 2,000 mg/kg males were significantly less than those of the vehicle control group. The Markov transition matrix analyses indicate female mice in the 2,000 mg/kg group had a significantly higher probability of extended estrus than did the vehicle control females. The incidences of hepatocytic hypertrophy were significantly increased in males and females in the 250 mg/kg or greater groups. Significantly increased incidences of focal hepatocytic necrosis occurred in 1,000 and 2,000 mg/kg males. The incidences of hyaline droplet accumulation in the respiratory epithelium of the nose were significantly increased in 500 mg/kg males and 1,000 and 2,000 mg/kg females. In the olfactory epithelium of the nose, the incidences of hyaline droplet accumulation were significantly increased in the 125 (female only), 500, and 1,000 mg/kg groups. Incidences of atrophy of the olfactory epithelium were significantly increased in the 1,000 mg/kg groups. The incidences of pigment accumulation in macrophages in the olfactory epithelium were significantly increased in males in the 500 mg/kg or greater groups and in 1,000 and 2,000 mg/kg females. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 0, 100, 300, or 1,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 104 or 105 (females) weeks. Additional groups of 10 male and 10 female rats (special study) were administered the same doses, 5 days per week for 14 weeks. Survival of 1,000 mg/kg males was significantly less than that of the vehicle controls. At week 14, all dosed groups of males and 1,000 mg/kg females had increased levels of thyroid stimulating hormone compared to those of the vehicle control groups. There were no significant decreases in the levels of triiodothyronine or total thyroxine. Mean body weights of 300 mg/kg males and females were less (10% or more) than those of the vehicle controls after week 93, and those of 1,000 mg/kg males and females were less after week 89. Clinical findings included ruffled fur in seven, eight, and 10 males in the 100, 300, and 1,000 mg/kg groups, respectively, beginning at week 89; four vehicle control males also had ruffled fur. Liver weights were significantly increased in all dosed groups of special study rats at 14 weeks. In the liver at 2 years, incidences of hepatocellular adenoma were slightly increased in 100 and 300 mg/kg males. Significantly increased incidences of nonneoplastic lesions at 2 years included hepatocyte hypertrophy and bile duct hyperplasia in all dosed groups of males and females, focal fatty change in all dosed groups of females, cystic degeneration in 100 and 1,000 mg/kg males, and oval cell hyperplasia and necrosis in 1,000 mg/kg males. In the thyroid gland, incidences of follicular cell adenoma were slightly increased in 300 and 1,000 mg/kg males and 300 mg/kg females. Single incidences of follicular cell carcinoma occurred in the 300 and 1,000 mg/kg female groups. There were significantly increased incidences of follicular cell hypertrophy in all dosed groups of males and females and follicle hyperplasia in all dosed groups of males. In the nose, adenoma of the respiratory epithelium occurred in two females receiving 300 mg/kg. Except for respiratory epithelium hyperplasia in 100 mg/kg females, the incidences of transitional epithelium and respiratory epithelium hyperplasia were significantly increased in all dosed groups of males and females. Except for olfactory epithelium respiratory metaplasia in 100 mg/kg females, the incidences of atrophy, respiratory metaplasia, nerve atrophy, and pigmentation were significantly increased in the olfactory epithelium of all dosed groups of males and females. Incidences of goblet cell hyperplasia in the respiratory epithelium were significantly increased in 300 and 1,000 mg/kg males and females, and incidences of chronic active inflammation were significantly increased in 1,000 mg/kg males and females. The incidence of submucosa fibrosis was significantly increased in 1,000 mg/kg males. The incidences of mononuclear cell leukemia in 300 and 1,000 mg/kg males were significantly greater than that in the vehicle controls. Dose-related increased severity of kidney nephropathy was noted in all dosed groups of males. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered 0, 200, 600, or 2,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 104 weeks. Survival of 600 and 2,000 mg/kg males was significantly less than that of the vehicle controls; survival of 600 mg/kg females was significantly greater than that of the vehicle controls. Mean body weights of 600 and 2,000 mg/kg males were less (10% or more) than those of the vehicle controls after weeks 85 and 77, respectively; mean body weights of 2,000 mg/kg females were generally less than those of the vehicle controls between weeks 17 and 69 and after week 93. In the liver, there were significantly increased incidences of hepatocellular adenoma in all dosed groups of females, hepatocellular carcinoma in all dosed groups of males and 2,000 mg/kg females, and hepatoblastoma in all dosed groups of males and 600 and 2,000 mg/kg females. The increased incidences of these neoplasms were primarily due to increased incidences of multiple adenoma, carcinoma, and hepatoblastoma. Except for the incidences of hepatocellular carcinoma or hepatoblastoma (combined) in 200 and 600 mg/kg females, the incidences of hepatocellular adenoma or carcinoma (combined), hepatocellular carcinoma or hepatoblastoma (combined), and hepatocellular adenoma, hepatocellular carcinoma, or hepatoblastoma (combined) were significantly increased in all dosed groups of males and females. Significantly increased incidences of nonneoplastic liver lesions included hypertrophy in all dosed groups of males and females, erythrophagocytosis in all dosed groups of males and in 600 and 2,000 mg/kg females, hematopoietic cell proliferation, inflammation, and necrosis in 600 and 2,000 mg/kg males, and cytoplasmic vacuolization, eosinophilic focus, and mixed cell focus in all dosed groups of females. In the thyroid gland, two incidences each of follicular cell adenoma occurred in the 600 and 2,000 mg/kg male groups. The incidence of follicle hyperplasia was significantly increased in 2,000 mg/kg males, and the incidences of follicular cell hypertrophy were significantly increased in 2,000 mg/kg males and 600 and 2,000 mg/kg females. In the forestomach, the incidences of inflammation, epithelium hyperplasia, and epithelium hyperkeratosis were significantly increased in all dosed groups of males and in 2,000 mg/kg females; the incidences of epithelium ulcer were significantly increased in 2,000 mg/kg males and females. GENETIC TOXICOLOGY Ginkgo biloba extract was mutagenic in S. typhimurium strains TA98 and TA100, and in E. coli strain WP2 uvrA/pKM101, with and without exogenous metabolic activation. (ABSTRACT TRUNCATED)
Subject(s)
Carcinogenesis/drug effects , Carcinogens/toxicity , Ginkgo biloba , Mutagens/toxicity , Plant Extracts/toxicity , Adenoma, Liver Cell/chemically induced , Adenoma, Liver Cell/pathology , Administration, Oral , Animals , Carcinogenicity Tests , Carcinogens/classification , Carcinogens/metabolism , DNA Damage , Escherichia coli/drug effects , Escherichia coli/genetics , Fatty Liver/chemically induced , Fatty Liver/pathology , Female , Ginkgo biloba/chemistry , Liver/drug effects , Liver/pathology , Liver Neoplasms/chemically induced , Liver Neoplasms/pathology , Male , Mice , Mice, Inbred Strains , Mutagenicity Tests , Mutagens/classification , Mutagens/metabolism , Mutation , Organ Size/drug effects , Plant Extracts/classification , Plant Extracts/metabolism , Rats , Rats, Inbred F344 , Salmonella typhimurium/drug effects , Salmonella typhimurium/geneticsABSTRACT
The National Toxicology Program (NTP) chronic inhalation bioassay of vanadium pentoxide (V(2)O(5)) produced "clear" evidence of lung tumors in B6C3F1 mice, but only "some" and "equivocal" evidence in male and female F344/N rats, respectively. No significant pairwise differences or trends with V(2)O(5) concentration in male or female rat poly-3-adjusted tumor incidence were reported. The "some" and "equivocal" evidence descriptors arose from comparisons of V(2)O(5)-exposed group incidence rates with NTP-2000- and NIH-07-fed historical control (HC) group incidence ranges. NTP acknowledged that use of data from NIH-07-fed HC groups could be inappropriate because the V(2)O(5) study used the NTP-2000 diet, but few studies using this newer diet were available then. We supplemented the early NTP-2000 diet HC data with data from 25 additional NTP-2000 diet studies conducted subsequent to the V(2)O(5) bioassay. This widened the HC tumor incidence ranges, thereby weakening the limited evidence for the carcinogenicity of inhaled V(2)O(5) in rats relative to HCs. The male rat control group in the V(2)O(5) study also appeared to be a near-"outlier" relative to the expanded HC database, potentially invalidating any comparisons of exposed group incidence rates with those for HCs. We conclude that there is "no" evidence of V(2)O(5) carcinogenicity in male or female F344/N rats.
Subject(s)
Adenocarcinoma/etiology , Adenoma/etiology , Carcinogens/toxicity , Data Interpretation, Statistical , Lung Neoplasms/etiology , Vanadium Compounds/toxicity , Adenocarcinoma/epidemiology , Adenocarcinoma/pathology , Adenoma/epidemiology , Adenoma/pathology , Administration, Inhalation , Animals , Carcinogenicity Tests , Carcinogens/classification , Dose-Response Relationship, Drug , Female , Lung Neoplasms/epidemiology , Lung Neoplasms/pathology , Male , Mice , Rats , Rats, Inbred F344 , Species Specificity , Time Factors , United States/epidemiology , Vanadium Compounds/classificationABSTRACT
Sitaxentan (Thelin®), an endothelin receptor antagonist with a long duration of action and high specificity for the endothelin receptor A subtype, was used to treat pulmonary arterial hypertension. It was withdrawn from the market due to an idiosyncratic risk of drug-induced liver injury identified from emerging clinical trial data and clinical case reports. The preclinical safety profile of sitaxentan is presented, including single- and repeat-dose toxicity in mice, rats, and dogs and carcinogenicity in mice and rats. Sitaxentan-related adverse effects included coagulopathy in rats and dogs, increased serum alkaline phosphatase activity in mice and dogs, and hepatic hypertrophy in all species. Decreased albumin, erythrocyte count, hemoglobin concentration and hematocrit, and increased coagulation times and liver weight were also noted. These effects generally occurred at systemic exposures (AUC(0-24)) that were substantially greater than those seen in humans. Twice-daily (vs. once daily) dosing resulted in increased toxicity, which correlated with increased trough plasma sitaxentan concentrations. Sitaxentan appeared to have a low potential for testicular and hepatic toxicity and was not carcinogenic. These studies suggested that sitaxentan would have a reasonable margin of safety when used as directed in humans and supported a positive benefit:risk assessment at the time of marketing approval.
Subject(s)
Antihypertensive Agents/toxicity , Carcinogens/toxicity , Endothelin Receptor Antagonists , Hypertension, Pulmonary/drug therapy , Isoxazoles/toxicity , Thiophenes/toxicity , Alkaline Phosphatase/blood , Animals , Antihypertensive Agents/classification , Antihypertensive Agents/pharmacokinetics , Blood Coagulation/drug effects , Carcinogenicity Tests , Carcinogens/classification , Carcinogens/pharmacokinetics , Chemical and Drug Induced Liver Injury, Chronic/etiology , Chemical and Drug Induced Liver Injury, Chronic/metabolism , Chemical and Drug Induced Liver Injury, Chronic/pathology , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Erythrocyte Indices/drug effects , Female , Hypertrophy/chemically induced , Hypertrophy/pathology , Isoxazoles/classification , Isoxazoles/pharmacokinetics , Liver/drug effects , Liver/pathology , Liver/physiopathology , Liver Function Tests , Male , Mice , Mice, Inbred Strains , Organ Size/drug effects , Rats , Rats, Sprague-Dawley , Risk Assessment , Species Specificity , Thiophenes/classification , Thiophenes/pharmacokineticsABSTRACT
Fusarium verticillioides causes several animal diseases and the contamination maize suggests that it could adversely affect human health. The fumonisin B mycotoxins were characterized from the fungal culture material and shown to be the causative principle responsible for the major mycotoxicological effects of the fungus in experimental and farm animals. The main focus was on the toxicological effects in rats and mice, the outcome of which played an important role in setting risk assessment parameters for exposure of the fumonisins to humans. The International Agency for Research on Cancer characterized the fumonisins as Group 2B carcinogens. Several controversial findings regarding the toxicological effects of the culture material of the fungus, the genotoxicity and carcinogenicity of pure fumonisin B(1) (FB(1)) in rats have been reported that should be clarified prior to assessing the risk in humans. The underlying differences between the diets with the high protein levels are likely to sensitize the kidneys to FB(1)-induced toxic and carcinogenic effects. Several other dietary factors, such as plant extracts (antioxidants) and dietary Fe, could either stimulate or inhibit cancer induction of FB(1), which complicates the comparison of toxicological effects in experimental animals. Cognisance should be taken of the modulating role of dietary constituents as it will determine the outcome of toxicological assays and determine the threshold of an adverse effect in a specific target organ to be used in determining risk assessment parameters.
Subject(s)
Carcinogens/toxicity , Fumonisins/toxicity , Mycotoxins/toxicity , Animals , Animals, Domestic , Carcinogens/classification , DNA/drug effects , Dietary Proteins/administration & dosage , Drug Interactions , Female , Food Contamination , Fumonisins/classification , Humans , Male , Mice , Mutagens/toxicity , Mycotoxins/classification , Rats , Risk AssessmentABSTRACT
Acrylamide, a known rodent and a probable human carcinogen, is spontaneously formed in foods cooked at high temperature. We studied the role of dietary acrylamide in modulating the early stages of colon carcinogenesis and assessed if dietary fat level was critical in altering the effects of acrylamide. Male F344 rats were subcutaneously injected with azoxymethane and were simultaneously randomized into 8 dietary groups (n=8 rats/group). Diets were based on AIN-93G semi-synthetic formula modified to contain either low fat (7% corn oil) or high fat (23.9% corn oil) and acrylamide at 0, 5, 10 or 50 mg/kg diet (wt/wt). All rats received the experimental diets ad libitum for 8 weeks, after which they were killed and their colons assessed for aberrant crypt foci (ACF), putative precancerous lesions. Irrespective of dietary fat level, rats with the highest tested dose of acrylamide (50 mg/kg diet) had significantly lower total ACF (p<0.05) and lower large ACF (those with 4 or more crypts/focus; p<0.001) compared with their respective controls (0 mg/kg diet). A significantly lower number of large ACF (p=0.046) was noted in rats treated with 10 mg/kg diet acrylamide exclusively in the high fat group, compared to the high fat control. This short-term bio-assay to test carcinogenicity of dietary acrylamide in the colon demonstrates that acrylamide, when administered through the diet at doses known to cause rat tumors, does not increase the risk of developing azoxymethane-induced precancerous lesions of the colon in rats. On the contrary, a high dose of dietary acrylamide decreased the growth of precancerous lesions in both low and high fat diet regimens in this model.
Subject(s)
Aberrant Crypt Foci/chemically induced , Acrylamide/toxicity , Carcinogens/toxicity , Colon/drug effects , Colorectal Neoplasms/chemically induced , Corn Oil/administration & dosage , Aberrant Crypt Foci/metabolism , Aberrant Crypt Foci/pathology , Acrylamide/classification , Animals , Azoxymethane/toxicity , Biomarkers, Tumor/metabolism , Carcinogens/classification , Caspase 9/metabolism , Colon/pathology , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Drug Interactions , Male , Proliferating Cell Nuclear Antigen/metabolism , Rats , Rats, Inbred F344ABSTRACT
BACKGROUND: Nuclear receptors (NR) are a superfamily of ligand-activated transcription factors that control a range of cellular processes. Persistent stimulation of some NR is a non-genotoxic mechanism of rodent liver cancer with unclear relevance to humans. Here we report on a systematic analysis of new in vitro human NR activity data on 309 environmental chemicals in relationship to their liver cancer-related chronic outcomes in rodents. RESULTS: The effects of 309 environmental chemicals on human constitutive androstane receptors (CAR/NR1I3), pregnane X receptor (PXR/NR1I2), aryl hydrocarbon receptor (AhR), peroxisome proliferator-activated receptors (PPAR/NR1C), liver X receptors (LXR/NR1H), retinoic X receptors (RXR/NR2B) and steroid receptors (SR/NR3) were determined using in vitro data. Hepatic histopathology, observed in rodents after two years of chronic treatment for 171 of the 309 chemicals, was summarized by a cancer lesion progression grade. Chemicals that caused proliferative liver lesions in both rat and mouse were generally more active for the human receptors, relative to the compounds that only affected one rodent species, and these changes were significant for PPAR (p0.001), PXR (p0.01) and CAR (p0.05). Though most chemicals exhibited receptor promiscuity, multivariate analysis clustered them into relatively few NR activity combinations. The human NR activity pattern of chemicals weakly associated with the severity of rodent liver cancer lesion progression (p0.05). CONCLUSIONS: The rodent carcinogens had higher in vitro potency for human NR relative to non-carcinogens. Structurally diverse chemicals with similar NR promiscuity patterns weakly associated with the severity of rodent liver cancer progression. While these results do not prove the role of NR activation in human liver cancer, they do have implications for nuclear receptor chemical biology and provide insights into putative toxicity pathways. More importantly, these findings suggest the utility of in vitro assays for stratifying environmental contaminants based on a combination of human bioactivity and rodent toxicity.
Subject(s)
Carcinogens/classification , Carcinogens/toxicity , Liver/drug effects , Receptors, Cytoplasmic and Nuclear/metabolism , Animals , Carcinoma, Hepatocellular/chemically induced , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Cells, Cultured , Constitutive Androstane Receptor , Disease Progression , Drug Evaluation, Preclinical/methods , Gene Expression/drug effects , Gene Expression Profiling , Gene Regulatory Networks/drug effects , High-Throughput Screening Assays/methods , Humans , Liver/metabolism , Liver/pathology , Liver Neoplasms/chemically induced , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Mice , Microarray Analysis , Rats , Receptors, Cytoplasmic and Nuclear/physiologyABSTRACT
An extensive toxicology programme on salmeterol hydroxynaphthoate (Serevent), a marketed long-acting beta(2)-adrenoceptor agonist, has been carried out. The studies evaluated both the local (respiratory tract) and systemic tolerance to single and repeated dosing, effects on all stages of reproduction, as well as the genotoxic and oncogenic potential. High acute doses were well tolerated and caused no specific target organ toxicity. In repeat dose studies, animals tolerated salmeterol very well both locally and systemically. No significant effects on the respiratory tract of dogs were seen and only minor laryngeal changes, typical of those occurring with many inhaled medicines, were noted in rats. The high systemic concentrations achieved resulted in a number of changes that are considered to be the result of excessive and prolonged beta( 2)-adrenoceptor stimulation. These included tachycardia, skeletal muscle hypertrophy and minor haematological and blood biochemical changes in general toxicity studies, foetal effects in rabbit organogenesis studies and increased incidences of smooth muscle tumours of the mesovarium in the rat and of the uterus in the mouse oncogenicity studies. Salmeterol showed no evidence of any genotoxic potential. Results of the extensive toxicology programme provide good assurance of the safety for the inhaled use of salmeterol in patients; this has ben confirmed by many years of clinical experience during its development and marketing.
Subject(s)
Adrenergic beta-Agonists/toxicity , Albuterol/analogs & derivatives , Carcinogens/toxicity , Mutagens/toxicity , Administration, Oral , Adrenergic beta-Agonists/administration & dosage , Adrenergic beta-Agonists/classification , Albuterol/administration & dosage , Albuterol/classification , Albuterol/toxicity , Animals , Animals, Inbred Strains , Carcinogens/administration & dosage , Carcinogens/classification , Dogs , Drug Evaluation, Preclinical , Female , Hypertrophy/chemically induced , Hypertrophy/pathology , Inhalation Exposure , Larynx/drug effects , Larynx/pathology , Male , Mice , Muscle, Skeletal/drug effects , Muscle, Skeletal/pathology , Mutagens/administration & dosage , Mutagens/classification , Rabbits , Rats , Reproduction/drug effects , Respiratory System/drug effects , Salmeterol Xinafoate , Tachycardia/chemically induced , Tachycardia/physiopathology , Toxicity TestsABSTRACT
Carcinogenic risk and molecular mechanisms underlying the liver tumor-promoting activity of copper gluconate, an additive of functional foods, were investigated using a rat medium-term liver carcinogenicity bioassay protocol (Ito test) and a 2-week short-term administration experiment. In the medium-term liver bioassay, Fischer 344 male rats were given a single i.p. injection of N-nitrosodiethylamine at a dose of 200 mg/kg b.w. as a carcinogenic initiator. Starting 2 weeks thereafter, rats received 0, 10, 300 or 6,000 ppm of copper gluconate in diet for 6 weeks. All rats underwent 2/3 partial hepatectomy at the end of week 3, and all surviving rats were killed at the end of week 8. In the short-term experiment, rats were given 0, 10, 300 or 6,000 ppm of copper gluconate for 2 weeks. Numbers of glutathione S-transferase placental form (GST-P) positive lesions, single GST-P-positive hepatocytes and 8-oxoguanine-positive hepatocytes, and levels of cell proliferation and apoptosis in the liver were significantly increased by 6,000 ppm of copper gluconate in the medium-term liver bioassay. Furthermore, hepatic mRNA expression of genes relating to the metal metabolism, inflammation and apoptosis were elevated by 6,000 ppm of copper gluconate both in the medium-term liver bioassay and the short-term experiments. These results indicate that copper gluconate possesses carcinogenic risk toward the liver at the high dose level, and that oxidative stress and inflammatory and pro-apoptotic signaling statuses may participate in its underlying mechanisms.
Subject(s)
Carcinogens/toxicity , Gluconates/toxicity , Liver Neoplasms/chemically induced , Liver/drug effects , Precancerous Conditions/chemically induced , Administration, Oral , Animals , Apoptosis/drug effects , Biological Assay , Carcinogenicity Tests , Carcinogens/classification , Carcinogens/metabolism , Cell Proliferation/drug effects , Diet , Dose-Response Relationship, Drug , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Gluconates/classification , Gluconates/metabolism , Glutathione Transferase/metabolism , Guanine/analogs & derivatives , Guanine/metabolism , Hepatectomy , Hepatocytes/drug effects , Hepatocytes/enzymology , Liver/metabolism , Liver/pathology , Liver Neoplasms/enzymology , Liver Neoplasms/pathology , Male , Metallothionein/genetics , Metallothionein/metabolism , Metals/metabolism , Oxidative Stress/drug effects , Precancerous Conditions/enzymology , Precancerous Conditions/pathology , RNA, Messenger/metabolism , Rats , Rats, Inbred F344ABSTRACT
Some have proposed that 2-year carcinogenicity studies may not be necessary if the material is a direct-acting DNA mutagen, induces liver enzymes, causes hyperplasia or toxicity in particular organs, causes cell proliferation, is cytotoxic, causes hormonal perturbations, or if one has QSAR analyses or 'omics information. Safety pharmacology data, pharmacologic activity, metabolism data, and results of 13-week dose ranging studies (with organ weight data, clinical chemistry data, hematologic data, clinical signs and histopathologic findings) were compared with results of 2-year carcinogenicity studies reviewed by the Center for Drug Evaluation and Research (CDER)/FDA. The experience with the ICH genetic toxicology battery and alternative carcinogenicity models was also reviewed. It appears that the information available from short-term studies is not currently sufficient to accurately and reliably predict the outcome of long-term carcinogenicity studies.
Subject(s)
Carcinogenicity Tests/methods , Carcinogens/adverse effects , Drug Evaluation, Preclinical/methods , Drug-Related Side Effects and Adverse Reactions , Predictive Value of Tests , Animals , Carcinogens/chemistry , Carcinogens/classification , Female , International Cooperation , Male , Mice , Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/classification , Rats , United States , United States Food and Drug AdministrationABSTRACT
FDA reviewers need a means to rapidly predict organ-specific carcinogenicity to aid in evaluating new chemicals submitted for approval. This research addressed the building of a database to use in developing a predictive model for such an application based on structure-activity relationships (SAR). The Internet availability of the Carcinogenic Potency Database (CPDB) provided a solid foundation on which to base such a model. The addition of molecular structures to the CPDB provided the extra ingredient necessary for SAR analyses. However, the CPDB had to be compressed from a multirecord to a single record per chemical database; multiple records representing each gender, species, route of administration, and organ-specific toxicity had to be summarized into a single record for each study. Multiple studies on a single chemical had to be further reduced based on a hierarchical scheme. Structural cleanup involved removal of all chemicals that would impede the accurate generation of SAR type descriptors from commercial software programs; that is, inorganic chemicals, mixtures, and organometallics were removed. Counterions such as Na, K, sulfates, hydrates, and salts were also removed for structural consistency. Structural modification sometimes resulted in duplicate records that also had to be reduced to a single record based on the hierarchical scheme. The modified database containing 999 chemicals was evaluated for liver-specific carcinogenicity using a variety of analysis techniques. These preliminary analyses all yielded approximately the same results with an overall predictability of about 63%, which was comprised of a sensitivity of about 30% and a specificity of about 77%.
Subject(s)
Carcinogens , Databases, Factual/standards , Organ Specificity , Structure-Activity Relationship , Animals , Carcinogens/adverse effects , Carcinogens/chemistry , Carcinogens/classification , Data Compression/methods , Data Compression/standards , Data Interpretation, Statistical , Discriminant Analysis , Drug Approval/organization & administration , Drug Evaluation, Preclinical , Humans , Internet , Liver/drug effects , Models, Chemical , Molecular Structure , Molecular Weight , Predictive Value of Tests , Sensitivity and Specificity , Toxicity Tests , Toxicology , United States , United States Food and Drug AdministrationABSTRACT
The incidence of renal tubule carcinogenesis in male and female rats or mice with 69 chemicals from the 513 bioassays conducted to date by the NCI/NTP has been collated, the chemicals categorized, and the relationship between carcinogenesis and renal tubule hyperplasia and exacerbation of the spontaneous, age-related rodent disease chronic progressive nephropathy (CPN) examined. Where information on mechanism or mode of action exists, the chemicals have been categorized based on their ability to directly or indirectly interact with renal DNA, or on their activity via epigenetic pathways involving either direct or indirect cytotoxicity with regenerative hyperplasia, or exacerbation of CPN. Nine chemicals were identified as directly interacting with DNA, with six of these producing renal tubule tumors at high incidence in rats of both sexes, and in some cases also in mice. Ochratoxin A was the most potent compound in this group, producing a high tumor incidence at very low doses, often with metastasis. Three chemicals were discussed in the context of indirect DNA damage mediated by an oxidative free radical mechanism, one of these being from the NTP database. A third category included four chemicals that had the potential to cause DNA damage following conjugation with glutathione and subsequent enzymatic activation to a reactive species, usually a thiol-containing entity. Two chemicals were allocated into the category involving a direct cytotoxic action on the renal tubule followed by sustained compensatory cell proliferation, while nine were included in a group where the cell loss and sustained increase in renal tubule cell turnover were dependent on lysosomal accumulation of the male rat-specific protein, alpha2mu-globulin. In a sixth category, morphologic evidence on two chemicals indicated that the renal tumors were a consequence of exacerbated CPN. For the remaining chemicals, there were no pertinent data enabling assignment to a mechanistic category. Accordingly, these chemicals, acting through an as yet unknown mechanism, were grouped as either being associated with an enhancement of CPN (category 7, 16 chemicals), or not associated with enhanced CPN (category 8, 4 chemicals). A ninth category dealt with 11 chemicals that were regarded as producing increases in renal tubule tumors that did not reach statistical significance. A 10th category discussed 6 chemicals that induced renal tumors in mice but not in rats, plus 8 chemicals that produced a low incidence of renal tubule tumors in mice that did not reach statistical significance. As more mechanistic data are generated, some chemicals will inevitably be placed in different groups, particularly those from categories 7 and 8. A large number of chemicals in the series exacerbated CPN, but those in category 7 especially may be candidates for inclusion in category 6 when further information is gleaned from the relevant NTP studies. Also, new data on specific chemicals will probably expand category 5 as cytotoxicity and cell regeneration are identified as obligatory steps in renal carcinogenesis in more cases. Additional confirmatory outcomes arising from this review are that metastases from renal tubule tumors, while encountered with chemicals causing DNA damage, are rare with those acting through an epigenetic pathway, with the exception being fumonisin B1; that male rats and mice are generally more susceptible than female rats and mice to chemical induction of renal tubule tumors; and that a background of atypical tubule hyperplasia is a useful indicator reflecting a chemically associated renal tubule tumor response. With respect to renal tubule tumors and human risk assessment, chemicals in categories 1 and 2, and possibly 3, would currently be judged by linear default methods; chemicals in category 4 (and probably some in category 3) as exhibiting a threshold of activity warranting the benchmark approach; and those in categories 5 and 6 as representing mechanisms that have no relevance for extrapolation to humans.
Subject(s)
Adenoma/chemically induced , Carcinogenicity Tests , Carcinogens/toxicity , Kidney Neoplasms/chemically induced , Kidney Tubules/drug effects , Adenoma/pathology , Animals , Carcinogens/classification , Carcinogens/metabolism , Databases, Factual , Female , Kidney Neoplasms/pathology , Kidney Tubules/pathology , Male , Mice , Mice, Inbred Strains , National Health Programs , National Institutes of Health (U.S.) , Rats , Rats, Inbred F344 , United StatesABSTRACT
On April 24, 2002 the Swedish National Food Administration along with a group of researchers at the University of Stockholm raised an alarm regarding potential health risks associated with eating fried and baked foods such as potatoes and bread. Scientists had found high levels of acrylamide (up to 500 times more acrylamide than that allowed in drinking water by the World Health Organisation), a substance widely believed to cause cancer, in cooked high starch foods. The outcomes of this "alarm" were immediate. In Sweden sales of chips fell by 30-50 percent over a 3-day period following the press conference, and share prices among several fried food manufacturers fell substantially, as stock analysts were fearful that consumption of fried foods would decrease significantly. Four days after the press conference, however, consumers began eating fried food as normal and a number of researchers and journalists in Sweden and elsewhere took the view that the alarm had been both exaggerated and ill placed. In this study, I evaluate the science communication process associated with the scare, based on a content analysis of a select group of Swedish broad sheets from just previous to the April 2002 press conference to the present time (December 2002). In addition, the study is based on interviews with the various Swedish regulators involved in the process itself (in particular at the Swedish National Food Administration) as well as with the scientists responsible for the study at Stockholm University and relevant journalists and politicians.
Subject(s)
Acrylamides/toxicity , Communication , Cooking/methods , Food Analysis/standards , Mass Media , Public Health Administration/standards , Risk Assessment/standards , Acrylamides/blood , Acrylamides/classification , Carcinogens/classification , Dietary Carbohydrates , Fear , Female , Humans , Solanum tuberosum , SwedenABSTRACT
The notice of intended change for the threshold limit value (TLV) for mineral oil mist contains a notation for human carcinogenicity. A description is provided of the current European regulatory approach used to distinguish between carcinogenic and non-carcinogenic mineral base oils on the basis of oil refining process and chemical marker information. This approach has proven effective in creating a market situation in the countries of the European Union where many customers require severely refined, non-carcinogenic oils. It is recommended that ACGIH consolidate the distinction between poorly and severely refined base oils in the recommended TLV for mineral oil mist and use different toxicological considerations to derive exposure control guidelines.
Subject(s)
Air Pollutants, Occupational/classification , Mineral Oil/classification , Petroleum/classification , Safety Management/legislation & jurisprudence , Air Pollutants, Occupational/standards , Carcinogens/classification , Europe , Government Regulation , Humans , Lubrication , Mineral Oil/toxicity , Petroleum/toxicity , Safety Management/methods , Threshold Limit ValuesSubject(s)
Mouth Neoplasms/classification , Mouth Neoplasms/pathology , Mouth Neoplasms/therapy , Analgesia , Brachytherapy , Carcinogens/classification , Dentistry , Drug Therapy , Drug Therapy/classification , Genes, Tumor Suppressor/physiology , Mouth Neoplasms , Mouth Neoplasms/complications , Mouth Neoplasms/diagnosis , Mouth Neoplasms/drug therapy , Mouth Neoplasms/epidemiology , Mouth Neoplasms/genetics , Mouth Neoplasms/immunology , Mouth Neoplasms/physiopathology , Mouth Neoplasms/prevention & control , Mouth Neoplasms/radiotherapy , Mouth Neoplasms/rehabilitation , Mouth Neoplasms/surgery , Head and Neck Neoplasms/therapy , Oncogenes/physiology , Osseointegration , Osseointegration/radiation effects , Osteoradionecrosis/etiology , Hyperbaric Oxygenation/methods , Prognosis , Chemoprevention/methods , Radiotherapy , Plastic Surgery Procedures , Retinoids/chemistry , Retinoids/pharmacologySubject(s)
Carcinogens/pharmacology , Drug-Related Side Effects and Adverse Reactions , Neoplasms, Experimental/chemically induced , Neoplasms/chemically induced , Animals , Carcinogens/classification , Carcinogens/toxicity , Drug Evaluation, Preclinical , Female , Humans , Male , Mice , Mutagenicity Tests , Pharmaceutical Preparations/classification , Rats , Structure-Activity RelationshipABSTRACT
Chemical carcinogens can be classified into two categories (i.e. mutagenic and non-mutagenic) on the basis of positive or negative evidence of DNA damage, mutagenicity or chromosomal aberrations in short-term test systems. Evidence indicates that carcinogenic peroxisome proliferators are negative in short-term test systems. This paper outlines approaches which may be useful in identifying a chemical carcinogen without mutagenic activity. It is conceivable that an alteration in DNA, if essential for initiation of neoplasia, may be mediated indirectly by the biological effects of nonmutagenic carcinogens.
Subject(s)
Carcinogens/classification , Microbodies/drug effects , Mutagens , Carcinogens/pharmacology , Drug Evaluation, Preclinical , In Vitro Techniques , Mutagenicity Tests , Salmonella typhimurium/geneticsABSTRACT
To evaluate the usefulness of the micronucleus test as a short-term assay for the detection of carcinogens, the correlation between micronucleus test data for 143 chemicals and corresponding cancer data, has been analyzed. For comparison, analogous data from Ames's test have also been collected for the same chemicals. In a comparison of the micronucleus test and Ames's test it was found that they had about the same specificity (around 80%) and predictive value (around 90%), while there was a significant difference in sensitivity in favor of Ames's test. The difference in sensitivity could be partly explained by differences in metabolizing capacities of these two test systems. It is concluded that a more elaborate test procedure for the micronucleus test would increase that sensitivity of this test. The principal value of the micronucleus test lies in the fact that it is an in vivo method, which may pick up effects at the chromosomal level not covered by bacterial assays. This is emphasized by the finding that the combination of Ames's test and the micronucleus test did increase the sensitivity of the screening procedure for the prediction of carcinogenic effects.
Subject(s)
Carcinogens , Cell Nucleus/drug effects , Mutagens , Animals , Carcinogens/classification , Drug Evaluation, Preclinical , Humans , Mutagens/classificationABSTRACT
A classification scheme is proposed for degrees of experimental evidence for the carcinogenicity of chemicals for animals. The classification stems from the suggestions of an IARC Working Group that the evaluation of bioassays include consideration of whether an increase in malignant tumours occurred and whether it occurred to an unusual degree or in multiple experiments. We extended the evaluative process to chemical experiments with no evidence of carcinogenicity and gave increased emphasis to results from more than one animal species. Although the proposed classification was developed for a group of NCI bioassays which were similar in design and conduct, it may provide a general framework for the evaluation of carcinogenesis bioassays and stimulate development and application of evaluative methods.