Increase In Lung Tumor Incidence Research Articles

High discordance in development and organ site distribution of tumors in rats and mice in NTP two-year inhalation studies

The National Toxicology Program (NTP) reports 60 two-year inhalation studies in both mice and rats on single agents or closely related agents. “Cadmium and cadmium compounds” and “diesel exhaust particulates” were omitted from this analysis due to lack of results regarding a particular compound. No Ames test data were available for antimony trioxide, nickel sulfate hexahydrate, and indium phosphide. For antimony trioxide, a comet assay was used as a surrogate for the Ames test. To eliminate selection bias, all positive Ames assay test results and any statistically significant increase in lung tumor incidence over background in an NTP two-year inhalation study were accepted at face value. For the 58 compounds tested via inhalation by NTP, there is a high degree of discordance between mice and rats in the susceptibility to develop lung tumors. The causation of tumors at anatomical sites outside the lung via the inhalation route is also discordant in mice and rats, for example, 11/58 (19%) of agents tested in the NTP inhalation studies using mice and rats were negative in the Ames assay test and showed lung tumors in mice only. The ability to form lung tumors in mice in the absence of genotoxicity demonstrates that other mechanisms, for example, cytotoxicity followed by reparative cellular proliferation, might be involved. Mouse and rat data are discordant regarding the ability to induce tumors at organ sites outside the lungs—0/58 as compared with 16/58, respectively. Mice and rats display distinctly different patterns of both lung tumor development and development of tumors outside the lungs.

Application of Genomic Biomarkers to Predict Increased Lung Tumor Incidence in 2-Year Rodent Cancer Bioassays

Rodent cancer bioassays are part of a legacy of safety testing that has not changed significantly over the past 30 years. The bioassays are expensive, time consuming, and use hundreds of animals. Fewer than 1500 chemicals have been tested in a rodent cancer bioassay compared to the thousands of environmental and industrial chemicals that remain untested for carcinogenic activity. In this study, we used existing data generated by the National Toxicology Program (NTP) to identify gene expression biomarkers that can predict results from a rodent cancer bioassay. A set of 13 diverse chemicals was selected from those tested by the NTP. Seven chemicals were positive for increased lung tumor incidence in female B6C3F1 mice and six were negative. Female mice were exposed subchronically to each of the 13 chemicals, and microarray analysis was performed on the lung. Statistical classification analysis using the gene expression profiles identified a set of eight probe sets corresponding to six genes whose expression correctly predicted the increase in lung tumor incidence with 93.9% accuracy. The sensitivity and specificity were 95.2 and 91.8%, respectively. Among the six genes in the predictive signature, most were enzymes involved in endogenous and xenobiotic metabolism, and one gene was a growth factor receptor involved in lung development. The results demonstrate that increases in chemically induced lung tumor incidence in female mice can be predicted using gene biomarkers from a subchronic exposure and may form the basis of a more efficient and economical approach for evaluating the carcinogenic activity of chemicals.

A/J Mouse As A Model For Lung Tumorigenesis Caused By Tobacco Smoke: Strengths And Weaknesses

Strain A/J mice have successfully been used to develop an animal model for tobacco smoke carcinogenesis. In 18 individual studies, reported by 4 different laboratories, a significant increase in lung tumor multiplicities following exposure from 50 to 170 mg/m3 of total suspended tobacco smoke particulates was found in 15 studies (83%) and a significant increase in lung tumor incidence in 10 studies (56%). However, tumor multiplicities are comparatively low (from an average of 1.1 to 2.8 tumors per lung). From a toxicological standpoint, this indicates that cigarette smoke is a weak animal carcinogen. Although the assay allowed one to detect substantial chemopreventive activity of a mixture of myo-inositol and dexamethasone, it was less successful in showing efficacy for several other agents.

Chronic Inhalation Toxicity of Size-Separated Glass Fibers in Fischer 344 Rats

Chronic Inhalation Toxicity of Size Separated Glass Fibers in Fischer 344 Rats. Hesterberg, T. W., Muller, W. C., McConnell E. E., Chevalier, J., Hadley, J. G., Bernstein, D. M., Thevenaz, P., and Anderson, R. (1993). Fundam. Appl. Toxicol. 20, 464-476.This is study was initiated to determine the chronic biological effects in Fisher 344 rats of inhaled size-separated respirable fractions of fibrous glass (FG) having compositions representative of common building insulation wools. Rats were exposed using nose-only inhalation chambers, 6 hr/day, 5 days/week, for 24 months to three concentrations(3, 16, and 30mg/m3)of two different compositions of FG (designated MMVF 10 and MMVF 11), or to filtered air (negative control). Fibrous glass findings were compared to those from a concurrent inhalation study of chrysotile asbestos and refractory ceramic fiber (RCF). The FGs used in this study were size selected to be largely respirable in the rat and the aerosol generation technique did not alter the dimensions of the fibers. Interim euthanizations look place at 3- to 6-month intervals to monitor progression of pulmonary changes. Fibers were recovered from digested lung tissue for determination of changes in fiber number and morphology. In animals exposed to 30 mg/m3 of MMVF 10 or MMVF 11, 4.2 ± 0.9 × 105 and 6.4 ±3. 1 × 105 fibers/mg dry lung tissue, respectively, were recovered after 24 months of exposure. Exposure to chrysotile asbestos (10 mg/m3) and to a lesser extent RCF (30 mg/m3) resulted in pulmonary fibrosis as well as mesothelioma and significant increases in lung tumors. FG exposure was associated with a nonspecific inflammatory response (macrophase response) in the lungs that did not appear to progress after 6-12 months of exposure. These cellular changes are reversible and are similar to the effects observed after inhalation of an inert dust. No lung fibrosis was observed in the FG-exposed animals. Further, FG exposure resulted in no mesotheliomas and no statistically significant increase in lung tumor incidence when compared to that of the negative control group. These findings, along with previous inhalation studies, suggest that respirable fibrous glass does not represent a significant hazard for fibrotic or neoplastic lung disease in humans.

Health Effects of Exposure to Diesel Engine Emissions: A Summary of Animal Studies Conducted by the U.S. Environmental Protection Agency's Health Effects Research Laboratories at Cincinnati, Ohio

In order to evaluate the potentially harmful effects of diesel engine emissions, inhalation exposure studies were carried out using a variety of animal species and strains, and measuring a wide range of toxicological parameters. Exhaust was provided by a 6 cylinder Nissan diesel engine operated 20 hours/day, 7 days/week, during a 2 month preliminary trial and 8 hours/day, 7 days/week during a 2 year, 4 month long-term study. The exhaust was diluted to produce a concentration of 6 mg/m3 particulate matter during the preliminary study and during the first year of the long term study and 12 mg/m3 thereafter. Exposure to diesel emissions did not result in detectable genotoxic effects as measured by increases in sister chromatid exchange (SCE), micronucleus testing and metaphase analysis in Chinese hamster and mouse bone marrow cells or in the morphology of cat sperm. SCE in lung cells from Syrian hamsters, however, was increased at the higher exposure level. The incidence of heritable mutations was not increased in mice. An increase in lung tumor incidence was detected in female Senear mice exposed from conception, but not in males, or in either male or female strain A mice exposed from 6 weeks of age. Voluntary activity was decreased in rats during exposure and learning ability was impaired in adult animals exposed during the early postnatal period. Susceptibility to an infectious challenge was increased in diesel exposed mice. Clearance of particles from the lung was found to be minimal even after 90 days recovery in clean air. Pulmonary function alterations in diesel exposed cats suggested the presence of a lesion restricting the air flow. The integrity of the lung as measured by leakage of 131I labeled protein into the alveoli did not seem to be impaired, but increased collagen synthesis suggested that fibrosis may develop with long-term exposure. The preliminary inhalation study resulted in the induction of xenobiotic metabolizing enzymes in the liver. In later studies, however, enzyme induction was found only in male mice injected with large doses of diesel particulate extract.

Tumors in CF-1 mice exposed for six consecutive generations to DDT.

CF-1 minimal inbred mice of 6 consecutive generations (parents, F1-F5) were fed 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (technical DDT) mixed into the diet at dose levels of 2, 10, 50, and 250 ppm for their lifespans. The experiment involved 3987 mice, including DDT-exposed and negative and positive controls. Exposure to all A levels of DDT significantly increased liver tumors (hepatomas) in males (50–55.9% in the 2, 10, and 250 ppm groups and 86% in the 250 ppm DDT groups, compared to 29.5% in controls). In females, hepatoma incidence increased considerably after exposure to 250 ppm DDT (65.5% compared to 4.7% in controls), whereas 10 and 50 ppm DDT only slightly increased the incidence (9 and 13%, respectively). No effect was noted at the level of 2 ppm DDT in females. The average lifespan of males with hepatomas decreased in DDT-treated groups (84 wk at the 250 ppm DDT level, 101–104 wk at the levels of 2, 10, and 50 ppm, as compared to 114 wk in controls). In females, only the highest dose level shortened the average lifespan of hepatoma-bearing mice (94 wk compared to 104 wk in controls). DDT did not alter tumor incidence at sites other than the liver, though an apparent, but not significant, increase in lung tumor incidence was noted at the levels of 2 and 10 ppm DDT. No progressive increase of hepatoma incidence from generation to generation was noted in DDT-treated mice. However, considerable variations in the incidence of tumors of the liver, lungs, and hematopoietic tissue were observed between the generations within each treatment group, including controls. One metastasizing hepatoma was found in controls and 13 in 4 DDT-treated groups. Malignant liver tumors, tentatively termed “hepato-blastomas,” also occurred, with a slightly increased incidence in the 10 and 50 ppm groups (3.9 and 3.1%, respectively, as compared to 0.9% in controls) and a significant increase in the 250 ppm group (7.1%). Ten of 56 tumors of this type found in DDT-treated mice metastasized to the lungs.