Lung Tumor Induction by 26-week Dermal Application of 1,2-Dichloroethane in CB6F1-Tg rasH2 Mice

Short-term alternatives to traditional 2-year carcinogenic studies in rodents are being actively pursued. Recently, a 26-week short-term carcinogenicity study using CB6F1-Tg rasH2@Jcl (rasH2) mice has become a worldwide standard for the evaluation of chemical carcinogenesis. However, an acceptable short-term carcinogenic study model for dermally applied products is still lacking. To investigate the suitability of using the rasH2 mouse to test carcinogenic potential, 1,2-dichloroethane (1,2-DCE) was dermally applied to rasH2 mice: 1,2-DCE is a known carcinogen that causes lung bronchiolo-alveolar adenomas and adenocarcinomas when administered topically, orally, or by inhalation exposure; 1,2-DCE at a dose level of 126 mg/mouse in 200 μl acetone or acetone alone (vehicle control) was applied to the dorsal skin of 10 mice of each sex 3 times a week for 26 weeks. As a positive control, 10 mice of each sex received a single intraperitoneal injection of 75 mg/kg of N-methyl- N-nitrosourea. Bronchiolo-alveolar adenomas and adenocarcinomas were significantly increased in 1,2-DCE-treated rasH2 mice of both sexes, and bronchiolo-alveolar hyperplasias were significantly increased in female mice. Overall, almost all mice of each sex developed adenomas and/or adenocarcinomas with 100% of female rasH2 mice developing bronchiolo-alveolar adenocarcinomas.

Download Full-text

Alternative Multiorgan Initiation–Promotion Assay for Chemical Carcinogenesis in the Wistar Rat

Toxicologic Pathology ◽

10.1177/0192623316678931 ◽

2016 ◽

Vol 44 (8) ◽

pp. 1146-1159

Author(s):

Marize de Lourdes Marzo Solano ◽

Noeme Souza Rocha ◽

Luis Fernando Barbisan ◽

Carla Adriene da Silva Franchi ◽

Ana Lúcia Tozzi Spinardi-Barbisan ◽

...

Keyword(s):

Chemical Carcinogenesis ◽

Wistar Rat ◽

Positive Control ◽

Fischer 344 ◽

Carcinogenic Potential ◽

Fischer 344 Rat ◽

Rat Strain ◽

Sodium Phenobarbital ◽

Academic Laboratory ◽

Positive Groups

The medium-term multiorgan initiation–promotion chemical bioassay (diethylnitrosamine, methyl-nitrosourea, butyl-hydroxybutylnitrosamine, dihydroxypropylnitrosamine, dimethylhydrazine [DMBDD]) with the Fischer 344 rat was proposed as an alternative to the conventional 2-year carcinogenesis bioassay for regulatory purposes. The acronym DMBDD stands for the names of five genotoxic agents used for initiation of multiorgan carcinogenesis. The Brazilian Agency for the Environment officially recognized a variation of this assay (DMBDDb) as a valid method to assess the carcinogenic potential of agrochemicals. Different from the original protocol, this DMBDDb is 30-week long, uses Wistar rats and two positive control groups exposed to carcinogenesis promoters sodium phenobarbital (PB) or 2-acetylaminofluorene (2-AAF). This report presents the experience of an academic laboratory with the DMBDDb assay and contributes to the establishment of this alternative DMBDD bioassay in a different rat strain. Frequent lesions observed in positive groups to evaluate the promoting potential of pesticides and the immunohistochemical expressions of liver cytochrome P450 (CYP) 2B1/2B2 and CYP1A2 enzymes were assessed. Commonly affected organs were liver, kidney, intestines, urinary bladder, and thyroid. PB promoting activity was less evident than that of 2-AAF, especially in males. This study provides a repository of characteristic lesions occurring in positive control animals submitted to a modified alternative 2-stage multiorgan protocol for carcinogenesis in Wistar rat.

Download Full-text

Mechanism of Action of TiO2: Recommendations to Reduce Uncertainties Related to Carcinogenic Potential

The Annual Review of Pharmacology and Toxicology ◽

10.1146/annurev-pharmtox-101419-100049 ◽

2021 ◽

Vol 61 (1) ◽

pp. 203-223 ◽

Cited By ~ 3

Author(s):

Hedwig M. Braakhuis ◽

Ilse Gosens ◽

Minne B. Heringa ◽

Agnes G. Oomen ◽

Rob J. Vandebriel ◽

...

Keyword(s):

Mechanism Of Action ◽

Animal Studies ◽

Inhalation Exposure ◽

Oral Route ◽

Oral Exposure ◽

Considerable Uncertainty ◽

Carcinogenicity Study ◽

Carcinogenic Potential ◽

Poorly Soluble ◽

Available Information

The Risk Assessment Committee of the European Chemicals Agency issued an opinion on classifying titanium dioxide (TiO2) as a suspected human carcinogen upon inhalation. Recent animal studies indicate that TiO2 may be carcinogenic through the oral route. There is considerable uncertainty on the carcinogenicity of TiO2, which may be decreased if its mechanism of action becomes clearer. Here we consider adverse outcome pathways and present the available information on each of the key events (KEs). Inhalation exposure to TiO2 can induce lung tumors in rats via a mechanism that is also applicable to other poorly soluble, low-toxicity particles. To reduce uncertainties regarding human relevance, we recommend gathering information on earlier KEs such as oxidative stress in humans. For oral exposure, insufficient information is available to conclude whether TiO2 can induce intestinal tumors. An oral carcinogenicity study with well-characterized (food-grade) TiO2 is needed, including an assessment of toxicokinetics and early KEs.

Download Full-text

Strain a Mouse Lung Tumor Bioassay

Journal of the American College of Toxicology ◽

10.3109/10915818209013138 ◽

1982 ◽

Vol 1 (1) ◽

pp. 145-169 ◽

Cited By ~ 49

Author(s):

Gary D. Stoner ◽

Michael B. Shimkin

Keyword(s):

Lung Tumor ◽

Mutagenic Activity ◽

Cell Types ◽

Mouse Lung ◽

Short Term ◽

Carcinogenic Activity ◽

Future Studies ◽

Carcinogenic Potential ◽

Mouse Lung Tissue ◽

Mouse Lung Tumor

This report summarizes data on the testing of 228 chemicals for carcinogenic activity by the strain A mouse lung adenoma bioassay. The assay is of six months duration and can distinguish two-fold dose differences in carcinogenic potential of compounds from a variety of chemical classes. Most compounds that induced lung tumors in strain A mice have also evoked a neoplastic response in other experimental animal bioassays and/or demonstrated mutagenic activity in various short-term tests. Recommendations are made for future studies on the: (a) distribution and metabolism of chemicals in strain A mouse lung tissue and in specific lung cell types, (b) ability of the lung adenoma bioassay to detect promoting agents, and (c) use of the bioassay to investigate the interactions of more than one chemical.

Download Full-text

Studies Evaluating the Utility of N-Methyl-N-Nitrosourea as a Positive Control in Carcinogenicity Studies in the p53+/– Mouse

International Journal of Toxicology ◽

10.1080/10915810500210385 ◽

2005 ◽

Vol 24 (5) ◽

pp. 349-356 ◽

Cited By ~ 7

Author(s):

Debie J. Hoivik ◽

Jane S. Allen ◽

Henry G. Wall ◽

James B. Nold ◽

Richard T. Miller ◽

...

Keyword(s):

Knockout Mice ◽

Positive Control ◽

Control Agent ◽

Mouse Bioassay ◽

Mesenteric Lymph Nodes ◽

Drug Candidates ◽

Carcinogenicity Study ◽

Mesenteric Lymph ◽

Carcinogenic Potential ◽

Papillary Hyperplasia

Studies conducted under the auspices of International Life Sciences Institute (ILSI) have suggested that an alternative mouse carcinogenicity study may be substituted for the traditional 2-year mouse bioassay typically conducted to support the development of drug candidates. The purpose of this study was to characterize the carcinogenic potential of N-methyl- N-nitrosourea (MNU), a DNA alkylating agent, in p53+ /– knockout mice to determine its suitability as a positive control agent in an alternative carcinogenicity model. p53+ /– knockout mice were administered a single oral dose of 90 mg/kg and maintained for up to 13 weeks prior to evaluation of neoplasms. Treatment was generally well tolerated; however, 4 of 30 mice died between the days of 75 and 92 due to neoplasms. MNU-related macroscopic observations included enlargement of the thymus, spleen, mandibular and mesenteric lymph nodes; and pale liver, heart, kidney, and bone marrow, which correlated with the diagnosis of lymphoma of the hematopoietic system, noted in the thymus of all affected animals and in the spleen, liver, lungs, and kidneys of some animals. Other treatment-related single neoplasms included a squamous-cell carcinoma in the nonglandular stomach and leiomyosarcoma in the glandular stomach. Non-neoplastic proliferative lesions included acanthosis and hyperkeratosis in the nonglandular stomach, focal papillary hyperplasia of the nonglandular stomach, glandular hyperplasia of the stomach, and adenomatous hyperplasia of the duodenum or ileum. The increased incidence of neoplastic and proliferative changes in MNU-treated mice suggests MNU could serve as a positive control in alternative carcinogenicity studies conducted in p53+ /– knockout mice.

Download Full-text

HAZARD: An Expert System for Risk Assessment of Environmental Chemicals

Methods of Information in Medicine ◽

10.1055/s-0038-1635482 ◽

1987 ◽

Vol 26 (01) ◽

pp. 13-23 ◽

Cited By ~ 2

Author(s):

H. W. Gottinger

Keyword(s):

Expert System ◽

Structural Information ◽

Chemical Carcinogenesis ◽

Structural Features ◽

Environmental Chemicals ◽

Chemical Carcinogens ◽

Carcinogenic Activity ◽

Current State ◽

Structure Activity ◽

Carcinogenic Potential

AbstractThe purpose of this paper is to report on an expert system in design that screens for potential hazards from environmental chemicals on the basis of structure-activity relationships in the study of chemical carcinogenesis, particularly with respect to analyzing the current state of known structural information about chemical carcinogens and predicting the possible carcinogenicity of untested chemicals. The structure-activity tree serves as an index of known chemical structure features associated with carcinogenic activity. The basic units of the tree are the principal recognized classes of chemical carcinogens that are subdivided into subclasses known as nodes according to specific structural features that may reflect differences in carcinogenic potential among chemicals in the class. An analysis of a computerized data base of known carcinogens (knowledge base) is proposed using the structure-activity tree in order to test the validity of the tree as a classification scheme (inference engine).

Download Full-text

IN VITRO METHODS FOR THE STUDY OF THE ADENOHYPOPHYSIAL FUNCTIONS TO SECRETE GONADOTROPHIN

Acta Endocrinologica ◽

10.1530/acta.0.068s027 ◽

1971 ◽

Vol 68 (1_Suppl) ◽

pp. S27-S40 ◽

Cited By ~ 1

Author(s):

T. Kobayashi ◽

T. Kigawa ◽

M. Mizuno ◽

T. Watanabe

Keyword(s):

Cell Culture ◽

Organ Culture ◽

Cultured Cells ◽

Cell Sheet ◽

Short Term ◽

Hypothalamic Extract ◽

Numerous Cell ◽

Single Cell Culture ◽

Almost All

ABSTRACT There are several in vitro methods to analyse the function of the adenohypophysis or the mechanisms of its regulation. The present paper deals with single cell culture, organ culture and short term incubation techniques by which the morphology and gonadotrophin-secreting function of the adenohypophysis were studied. In trypsin-dispersed cell culture, the adenohypophysial cells showed extensive propagation to form numerous cell colonies and finally develop into a confluent monolayer cell sheet covering completely the surface of culture vessels. Almost all of the cultured cells, however, became chromophobic, at least at the end of the first week of cultivation, when gonadotrophin was detectable neither in the culture medium nor in the cells themselves. After the addition of the hypothalamic extract, gonadotrophin became detectable again, and basophilic or PAS-positive granules also reappeared within the cells, suggesting that the gonadotrophs were stimulated by the extract to produce gonadotrophin. In organ culture and short term incubation, the incorporation of [3H] leucine into the adenohypophysial cells in relation to the addition of hypothalamic extract was examined. It was obvious that the ability to incorporate [3H] leucine into the gonadotrophs in vitro was highly dependent upon the presence of the hypothalamic extract.

Download Full-text

Proposal to Eliminate Urethane-Treated Positive Control Dose Groups in 26-Week Tg.rasH2 Carcinogenicity Studies

International Journal of Toxicology ◽

10.1177/10915818211003308 ◽

2021 ◽

pp. 109158182110033

Author(s):

Madhav G. Paranjpe ◽

Daniel Rudmann ◽

Aaron Sargeant ◽

Mark Morse ◽

Rossalin Yonpiam ◽

...

Keyword(s):

Alternative Model ◽

Positive Control ◽

Short Term ◽

Control Material ◽

Pilot Studies ◽

Cumulative Experience ◽

Observation Period

Short-term (26 weeks) Tg.rasH2 mouse carcinogenicity studies have been conducted as an alternative model to the conventional 2-year mouse carcinogenicity studies, using urethane as a positive control material. In these studies, urethane was used at a dose of 1,000 mg/kg/dose, administered intraperitoneally on days 1, 3, and 5. Urethane consistently produces lung adenomas and carcinomas and hemangiosarcomas of the spleen, proving validity of the assay. We conducted 3 pilot studies at 3 different sites of Charles River Laboratories using a lower dose of urethane (500 mg/kg/dose), administered on days 1, 3, and 5, followed by a 12-week observation period. Our results demonstrate that a lower dose can be used successfully with fewer number of animals per sex to prove the validity of the assay. However, based on our cumulative experience with this model, we propose to eliminate positive control dose groups in future Tg.rasH2 carcinogenicity studies.

Download Full-text

Transcriptional profiling reveals gene expression changes associated with inflammation and cell proliferation following short-term inhalation exposure to copper oxide nanoparticles

Journal of Applied Toxicology ◽

10.1002/jat.3548 ◽

2017 ◽

Vol 38 (3) ◽

pp. 385-397 ◽

Cited By ~ 16

Author(s):

Pedro M. Costa ◽

Ilse Gosens ◽

Andrew Williams ◽

Lucian Farcal ◽

Daniele Pantano ◽

...

Keyword(s):

Gene Expression ◽

Cell Proliferation ◽

Copper Oxide ◽

Transcriptional Profiling ◽

Inhalation Exposure ◽

Copper Oxide Nanoparticles ◽

Oxide Nanoparticles ◽

Short Term

Download Full-text

Long-term effects of carbon containing engineered nanomaterials and asbestos in the lung: one year postexposure comparisons

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00167.2013 ◽

2014 ◽

Vol 306 (2) ◽

pp. L170-L182 ◽

Cited By ~ 82

Author(s):

Anna A. Shvedova ◽

Naveena Yanamala ◽

Elena R. Kisin ◽

Alexey V. Tkach ◽

Ashley R. Murray ◽

...

Keyword(s):

Lung Tumor ◽

Inhalation Exposure ◽

Geometric Feature ◽

Width Ratio ◽

Long Term Effects ◽

Genotoxic Effects ◽

Pulmonary Exposure ◽

Pharyngeal Aspiration

The hallmark geometric feature of single-walled carbon nanotubes (SWCNT) and carbon nanofibers (CNF), high length to width ratio, makes them similar to a hazardous agent, asbestos. Very limited data are available concerning long-term effects of pulmonary exposure to SWCNT or CNF. Here, we compared inflammatory, fibrogenic, and genotoxic effects of CNF, SWCNT, or asbestos in mice 1 yr after pharyngeal aspiration. In addition, we compared pulmonary responses to SWCNT by bolus dosing through pharyngeal aspiration and inhalation 5 h/day for 4 days, to evaluate the effect of dose rate. The aspiration studies showed that these particles can be visualized in the lung at 1 yr postexposure, whereas some translocate to lymphatics. All these particles induced chronic bronchopneumonia and lymphadenitis, accompanied by pulmonary fibrosis. CNF and asbestos were found to promote the greatest degree of inflammation, followed by SWCNT, whereas SWCNT were the most fibrogenic of these three particles. Furthermore, SWCNT induced cytogenetic alterations seen as micronuclei formation and nuclear protrusions in vivo. Importantly, inhalation exposure to SWCNT showed significantly greater inflammatory, fibrotic, and genotoxic effects than bolus pharyngeal aspiration. Finally, SWCNT and CNF, but not asbestos exposures, increased the incidence of K-ras oncogene mutations in the lung. No increased lung tumor incidence occurred after 1 yr postexposure to SWCNT, CNF, and asbestos. Overall, our data suggest that long-term pulmonary toxicity of SWCNT, CNF, and asbestos is defined, not only by their chemical composition, but also by the specific surface area and type of exposure.

Download Full-text