In a subchronic (13-week) inhalation toxicity study with a terminal sacrifice (after 13 weeks inhalation) and several recovery period sacrifices (13, 26, 39, and 52 weeks), the effects of AEROSIL® 200 (pyrogenic synthetic amorphous silica (SAS)), AEROSIL® R 974 (surface-treated pyrogenic SAS), and SIPERNAT® 22 S (precipitated SAS) were tested in rats at multiple dose levels. The aforementioned materials are all SAS products. A comparative group of animals was exposed to quartz dust. This study attempts to reexamine the lung tissues originally evaluated in a study published by Reuzel et al. using the current standards. To reach a high level of credibility, the results of the reevaluation were subsequently examined by a pathology working group (PWG). In particular, the reevaluating pathologist and the PWG concluded that, even though quartz (crystalline silica) persisted, induced alterations in the lungs following 13 weeks of exposure to amorphous silicas were reversible following 52 weeks of recovery. A long-term adversity has not been established with SAS products. However, quartz dust damages lungs significantly by causing pulmonary fibrosis.

Bentonite, a clay with numerous industrial and consumer applications, is mined and processed in many countries of the world. Its many beneficial uses also create the potential for widespread occupational and consumer exposure. The available studies on toxicity and epidemiology indicate that the principal exposure pathway of concern is inhalation of respirable dust by occupationally exposed cohorts. Bentonite itself is probably not more toxic than any other particulate not otherwise regulated and is not classified as a carcinogen by any regulatory or advisory body, but some bentonite may contain variable amounts of respirable crystalline silica, a recognized human carcinogen. Therefore, prudent management and adherence to occupational exposure limits is appropriate. This review summarizes the literature available on production, applications, exposure, toxicity, and epidemiology of bentonite and identifies data gaps and limitations.

A rat carcinogenicity bioassay (CaBio) of quinacrine was reanalyzed to investigate its mode of tumor induction. Quinacrine’s effects in the rat uterus when administered as a slurry in methylcellulose were contrasted with the human clinical experience which uses a solid form of the drug, to determine the relevance of the tumors produced in the rat to safe clinical use of quinacrine for permanent contraception (QS). A review was performed of the study report, dose feasibility studies, and clinical evaluations of women who had undergone the QS procedure. The top three doses of quinacrine in the CaBio exceeded the maximum tolerated dose, and produced chronic damage, including inflammation, resulting in reproductive tract tumors. Chronic inflammation was significantly correlated with the tumors; there was no evidence of treatment-related tumors in animals without chronic inflammation or other reproductive system toxicity. Because such permanent uterine damage and chronic toxicity have not been observed in humans under therapeutic conditions, we conclude that this mode of action for tumor production will not occur at clinically relevant doses in women who choose quinacrine for permanent contraception.

1,4-Dioxane is found in consumer products and is used as a solvent in manufacturing. Studies in rodents show liver tumors to be consistently reported after chronic oral exposure. However, there were differences in the reporting of non-neoplastic lesions in the livers of rats and mice. In order to clarify these differences, a reread of mouse liver slides from the 1978 NCI bioassay on 1,4-dioxane in drinking water was conducted. This reread clearly identified dose-related non-neoplastic changes in the liver; specifically, a dose-related increase in the hypertrophic response of hepatocytes, followed by necrosis, inflammation and hyperplastic hepatocellular foci. 1,4-Dioxane does not cause point mutations, DNA repair, or initiation. However, it appears to promote tumors and stimulate DNA synthesis. Using EPA Guidelines (2005), the weight of the evidence suggests that 1,4-dioxane causes liver tumors in rats and mice through cytotoxicity followed by regenerative hyperplasia. Specific key events in this mode of action are identified. A Reference Dose (RfD) of 0.05mg/kgday is proposed to protect against regenerative liver hyperplasia based on a benchmark dose (BMD) approach. Based on this RfD, a maximum contaminant level goal of 350μg/L is proposed using a default relative source contribution for water of 20%.

Perfluorooctanoate (PFO) is a perfluorinated carboxylate that is widely distributed in the environment. A 2-year chronic study was conducted in rats fed either 30 or 300 ppm of ammonium perfluorooctanoate (APFO). To investigate the possible relationship of APFO exposure to proliferative mammary lesions, a Pathology Working Group (PWG) review of the original slides was performed. The consensus reached by the PWG was that the incidence of mammary-gland neoplasms was not affected by chronic dietary administration of APFO. Therefore, feeding female rats up to 300 ppm of APFO resulted in no increase in proliferative lesions of the mammary tissue.

This companion article offers an alternative interpretation for the quinacrine-induced uterine tumors observed in a 2-year bioassay in rats (CaBio, Cancel et al., 2010), and provides additional data from two new experiments that support a different interpretation and analysis. Our major premise is that the design of the Cancel et al. bioassay was flawed, particularly regarding dose selection that allowed for misinterpretation of carcinogenic activity. We feel the totality of the information provided herein dictates that the doses (70/70, 70/250 and 70/350 mg/kg quinacrine) causing uterine tumors in their study clearly exceeded the maximum tolerated dose (MTD) typically administered in chronic cancer studies. Our new data support this conclusion and serve to explain the development of lesions, especially the uterine tumors, they have reported. We argue that the rat uterus is not a valid surrogate for the human fallopian tube. Further, we maintain that quinacrine is not genotoxic in vivo, as suggested in their paper. In summary, we believe that quinacrine is not carcinogenic in rats at doses that do not exceed the MTD.

Environmental and Molecular MutagenesisVolume 50, Issue 1 p. 1-3 Letter to the EditorFree Access Mycoplasma pulmonis and lymphoma Trenton R. Schoeb, Trenton R. Schoeb Department of Genetics, University of Alabama at Birmingham, Birmingham, AlabamaSearch for more papers by this authorErnest E. McConnell, Ernest E. McConnell ToxPath, Inc., Raleigh, North CarolinaSearch for more papers by this authorM. Margaret Juliana, M. Margaret Juliana Department of Genetics, University of Alabama at Birmingham, Birmingham, AlabamaSearch for more papers by this authorJerry K. Davis, Jerry K. Davis Department of Comparative Pathobiology, Purdue University, West Lafayette, IndianaSearch for more papers by this authorMaureen K. Davidson, Maureen K. Davidson U. S. Food and Drug Administration, Silver Spring, MarylandSearch for more papers by this authorJ. Russell Lindsey, J. Russell Lindsey Emeritus, University of Alabama at Birmingham, Birmingham, AlabamaSearch for more papers by this author Trenton R. Schoeb, Trenton R. Schoeb Department of Genetics, University of Alabama at Birmingham, Birmingham, AlabamaSearch for more papers by this authorErnest E. McConnell, Ernest E. McConnell ToxPath, Inc., Raleigh, North CarolinaSearch for more papers by this authorM. Margaret Juliana, M. Margaret Juliana Department of Genetics, University of Alabama at Birmingham, Birmingham, AlabamaSearch for more papers by this authorJerry K. Davis, Jerry K. Davis Department of Comparative Pathobiology, Purdue University, West Lafayette, IndianaSearch for more papers by this authorMaureen K. Davidson, Maureen K. Davidson U. S. Food and Drug Administration, Silver Spring, MarylandSearch for more papers by this authorJ. Russell Lindsey, J. Russell Lindsey Emeritus, University of Alabama at Birmingham, Birmingham, AlabamaSearch for more papers by this author First published: 23 December 2008 https://doi.org/10.1002/em.20465Citations: 6AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume50, Issue1January 2009Pages 1-3 ReferencesRelatedInformation

There is controversy over whether low doses of bisphenol A (BPA, CAS no. 80-05-7) cause reproductive and developmental effects in humans. We update the 2004 weight-of-evidence assessment of an expert panel convened by Harvard's Center for Risk Analysis by critically evaluating over 50 additional studies published between April 2002 and February 2006 that examine in vivo reproductive and developmental toxicity in mammals at doses ≤5 mg/kg-d. Our findings are consistent with the Harvard study: some statistically significant findings in rats and mice exist but they are generally countered by more numerous studies showing no effect for similar endpoints. No effect is marked or consistent across species, doses, and time points. Some mouse studies report morphological changes in testes and sperm and some non-oral mouse studies report morphological changes in female reproductive organs. Owing to lack of first-pass metabolism, results from non-oral studies are of limited relevance to oral human exposure. Human biomonitoring indicates exposures lower than the "low" doses in the reviewed animal studies. Reports of human health impact are very limited and inconsistent. Taken together, the weight of evidence does not support the hypothesis that low oral doses of BPA adversely affect human reproductive and developmental health.

Experimental animal studies comparing asbestos and non-asbestos varieties of tremolite indicate tremolite asbestos is markedly more carcinogenic. By direct analogy, the differences in carcinogenicity between tremolite asbestos and non-asbestos prismatic tremolite should be the same for the other types of amphibole that also crystallize in the asbestos and non-asbestos habits. The earliest of the experiment animal studies, done more than 25 years ago, have design limitations by modern standards including the use of injection or surgical implantation as the route of administration rather than the more relevant route of inhalation. However, the differences in the carcinogenicity of amphibole asbestos and non-asbestos amphiboles are sufficiently large to be clearly discernable even with the study limitations. Together with later studies on these and related minerals, there is strong evidence of a much lower hazard associated with the shorter, thicker fibers of the non-asbestos amphiboles, than is found for the asbestos analogues of the same mineral. It is possible that the non-asbestos amphiboles are no more hazardous than other silicate minerals widely considered nuisance dusts.

In the early 1970s, it became a concern that exposure to the mineral fibers associated taconite ore processed in Silver Bay, Minnesota would cause asbestos-related disease including gastrointestinal cancer. At that time data gaps existed which have now been significantly reduced by further research. To further our understanding of the types of airborne fibers in Silver Bay we undertook a geological survey of their source the Peter Mitchell Pit, and found that there are no primary asbestos minerals at a detectable level. However we identified two non-asbestos types of fibrous minerals in very limited geological locales. Air sampling useful for risk assessment was done to determine the type, concentrations and size distribution of the population of airborne fibers around Silver Bay. Approximately 80% of the airborne fibers have elemental compositions consistent with cummingtonite-grunerite and the remaining 20% have elemental compositions in the tremolite-actinolite series. The mean airborne concentration of both fiber types is less than 0.00014 fibers per milliliter that is within the background level reported by the World Health Organization. We calculate the risk of asbestos-related mesothelioma and lung cancer using a variety of different pessimistic assumptions. (i) that all the non-asbestos fibers are as potent as asbestos fibers used in the EPA-IRIS listing for asbestos; with a calculated risk of asbestos-related cancer for environmental exposure at Silver Bay of 1 excess cancer in 28,500 lifetimes (or 35 excess cancers per 1,000,000 lifetimes) and secondly that taconite associated fibers are as potent as chrysotile the least potent form of asbestos. The calculated risk is less than 0.77 excess cancer case in 1,000,000 lifetimes. Finally, we briefly review the epidemiology studies of grunerite asbestos (amosite) focusing on the exposure conditions associated with increased risk of human mesothelioma.

A proposal has been developed by the Agricultural Chemical Safety Assessment (ACSA) Technical Committee of the ILSI Health and Environmental Sciences Institute (HESI) for an improved approach to assessing the safety of crop protection chemicals. The goal is to ensure that studies are scientifically appropriate and necessary without being redundant, and that tests emphasize toxicological endpoints and exposure durations that are relevant for risk assessment. The ACSA Systemic Toxicity Task Force proposes an approach to systemic toxicity testing as one part of the overall assessment of a compound's potential to cause adverse effects on health. The approach is designed to provide more relevant data for deriving reference doses for shorter time periods of human exposure, and includes fewer studies for deriving longer term reference doses-that is, neither a 12-month dog study nor a mouse carcinogenicity study is recommended. All available data, including toxicokinetics and metabolism data and life stages information, are taken into account. The proposed tiered testing approach has the potential to provide new risk assessment information for shorter human exposure durations while reducing the number of animals used and without compromising the sensitivity of the determination of longer term reference doses.

This working group report is the product of the joint efforts of the members of an expert working group organized and convened by the International Life Sciences Institute Risk Science Institute. A...

Wollastonite is a naturally occurring calcium silicate (CaSiO3) that is produced in both powder and fibrous forms. It is a valuable industrial mineral used in plastics, ceramics, metallurgical applications, paint, and friction products. For some applications wollastonite serves as an asbestos replacement. To varying degrees, wollastonite grades contain respirable particles/fibers, some of which have lengths and diameters that might be biologically active if deposited and retained in the lung. In this review we provide background information on wollastonite properties, markets, production and use, regulatory classification, and occupational exposure limits. We also summarize the available studies on the toxicology and epidemiology of wollastonite. We conclude that there is inadequate evidence for the carcinogenicity of wollastonite in animals and, based on strong evidence that wollastonite is not biopersistent, believe that a well-designed animal inhalation bioassay would have a negative result. The epidemiological evidence for wollastonite is limited, but does not suggest that workers are at significant risk of an increased incidence of pulmonary fibrosis, lung cancer, or mesothelioma. Morbidity studies have demonstrated a nonspecific increase in bronchitis and reduced lung function. It is prudent, however, to continue product stewardship efforts by wollastonite producers to control workplace exposures and to monitor scientific developments.

Wollastonite is a naturally occurring calcium metasilicate acicular mineral that is used in a variety of commercial applications and has been proposed as an asbestos substitute for selected products. Male Fischer 344 rats were exposed by inhalation to 10 mg/m3 (360 fibers/cm3) wollastonite (NYAD-G) for 6 h/d, 5 d/wk for 12 or 24 mo. They were compared to untreated chamber controls and positive controls [chrysotile asbestos, 70 mg/m3 (-7000 fibers/cm3) for 12 mo]. Six rats from each exposure group were killed after 3, 12, and 24 mo. The remaining rats were held for lifetime observation (until 90% mortality). The results of this study showed that wollastonite was slightly toxic to the lung, producing an alveolar macrophage response that resolved after exposure ceased. There was no evidence of wohstonite-induced neoplasms, although the chrysotile asbestos administered under similar conditions produced a high incidence of bronchoalveolar carcinomas.

Annals of the New York Academy of SciencesVolume 534, Issue 1 p. 648-662 Chronic Toxkity Results and Ongoing Studies of 1,3-Butadiene by the National Toxicology Program R. L. MELNICK, R. L. MELNICK National Toxicology Program National Institute of Environmental Health Sciences Research Triangle Park, North Carolina 27709Search for more papers by this authorJ. E. HUFF, J. E. HUFF National Toxicology Program National Institute of Environmental Health Sciences Research Triangle Park, North Carolina 27709Search for more papers by this authorJ. K. HASEMAN, J. K. HASEMAN National Toxicology Program National Institute of Environmental Health Sciences Research Triangle Park, North Carolina 27709Search for more papers by this authorE. E. McCONNELL, E. E. McCONNELL National Toxicology Program National Institute of Environmental Health Sciences Research Triangle Park, North Carolina 27709Search for more papers by this author R. L. MELNICK, R. L. MELNICK National Toxicology Program National Institute of Environmental Health Sciences Research Triangle Park, North Carolina 27709Search for more papers by this authorJ. E. HUFF, J. E. HUFF National Toxicology Program National Institute of Environmental Health Sciences Research Triangle Park, North Carolina 27709Search for more papers by this authorJ. K. HASEMAN, J. K. HASEMAN National Toxicology Program National Institute of Environmental Health Sciences Research Triangle Park, North Carolina 27709Search for more papers by this authorE. E. McCONNELL, E. E. McCONNELL National Toxicology Program National Institute of Environmental Health Sciences Research Triangle Park, North Carolina 27709Search for more papers by this author First published: June 1988 https://doi.org/10.1111/j.1749-6632.1988.tb30155.xCitations: 9AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Kirshenbaum, I. 1979. Butadiene. In Kirk-Othmer Encyclopedia of Chemical Technology, ed. 3; 4: 313–337. John Wiley and Sons. New York . 2 Kirshenbaum, I. C & En's top 50 chemical products. 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Species differences in butadiene metabolism between mice and rats evaluated by inhalation pharmacokinetics. Arch. Toxicol. 58: 235–238. 35 International Agency for Research on Cancer. 1986. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. 39. Some chemicals used in plastics and elastomers. 1,3-Butadiene. 155–179. Lyon , France . 36 Thurmond, L. M., L. D. Lauer, R. V. House, W. S. Stillman, R. D. Irons, W. H. Steinhagen & J. H. Dean. 1986. Effects of short-term inhalation exposure to 1,3-butadiene on murine immune functions. Toxicol. Appl. Pharmacol. 86: 170–179. 37 Ito, N., T. Ogiso, S. Fukushima, M. Shibata & A. Hagiwara. 1984. Carcinogenicity of captafol in B6C3F1 mice. Gann 75: 853–865. 38 Andjelkovich, D., J. Taulbee & M. Symons. 1976. Mortality experience of acohort of rubber workers, 1964–1973. J. Occup. Med. 18: 387–394. 39 McMichael, A. J., R. Spiritas, J. F. Gamble & P. M. Tousey. 1976. Mortality among rubber workers: Relationship to specific jobs. J. Occup. Med. 18: 178–185. 40 Matanoski, G. M., L. Schwartz, J. Sperrazza & J. Tonascia, 1982. Mortality of workers in the styrene-butadiene rubber polymer manufacturing industry. Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD. Unpublished. 41 Meinhardt, T. J., R. A. Lemen, M. S. Crandall & R. J. Young. 1982. Environmental epidemiologic investigation of the styrene-butadiene rubber industry. Scand. J. Work Environ. Health 8: 250–259. 42 U.S. Environmental Protection Agency. 1985. Mutagenicity and carcinogenicity assessment of 1,3-butadiene. EPA/600/8-85/004F. Washington , DC . Citing Literature Volume534, Issue1Living in a Chemical World: Occupational and Environmental Significance of Industrial CarcinogensJune 1988Pages 648-662 ReferencesRelatedInformation