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Hardisty J.F.,Experimental Pathology Laboratories EPL | Willson G.A.,Experimental Pathology Laboratories EPL | McConnell E.E.,ToxPath Inc. | Frame S.R.,United Health Centers | And 3 more authors.
Drug and Chemical Toxicology | Year: 2010

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. © 2010 Informa UK Ltd.


Maxim L.D.,Everest Consulting Associ. | Niebo R.,Everest Consulting Associ. | Utell M.J.,University of Rochester | McConnell E.E.,ToxPath Inc. | And 2 more authors.
Inhalation Toxicology | Year: 2014

This review updates earlier work addressing the epidemiology and toxicity of wollastonite. Earlier chronic animal bioassay and human mortality data were inadequate (IARC term) or negative and no new studies of these types have been published. Wollastonite has been determined to have low biopersistence in both in vivo and in vitro studies, which probably accounts for its relative lack of toxicity. Earlier morbidity studies of mining/mineral processing facilities in Finland and New York State indicated that exposure to wollastonite might result in pleural plaques (Finland) or decrements in certain measures of lung function (New York). More recent analysis of data from an ongoing health surveillance program at one facility (New York) indicates that there are no pleural plaques or interstitial lung disease or decrements in lung function among never smokers or former smokers occupationally exposed to wollastonite. This result probably reflects continued reduction in exposures as part of an ongoing product stewardship program at this facility and suggests that wollastonite has relatively low toxicity as currently managed. © 2014 Informa Healthcare USA, Inc. All rights reserved.


Haseman J.K.,J.K. Haseman Consulting | Growe R.G.,International Federation for Family Health | Zeiger E.,Errol Zeiger Consulting | McConnell E.E.,Toxpath Inc. | And 2 more authors.
Regulatory Toxicology and Pharmacology | Year: 2015

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. © 2015 The Authors.


PubMed | International Federation for Family Health, Errol Zeiger Consulting, Toxpath Inc., J.K. Haseman Consulting and 2 more.
Type: Journal Article | Journal: Regulatory toxicology and pharmacology : RTP | Year: 2015

A rat carcinogenicity bioassay (CaBio) of quinacrine was reanalyzed to investigate its mode of tumor induction. Quinacrines 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.


McConnell E.E.,ToxPath Inc | Lippes J.,Hampton University | Growe R.G.,International Services Assistance Fund | Fail P.,Patricia Fail Associates | And 2 more authors.
Regulatory Toxicology and Pharmacology | Year: 2010

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. © 2010 Elsevier Inc.


Maxim L.D.,15 North Main St. | Niebo R.,15 North Main St. | Mcconnell E.E.,ToxPath Inc.
Inhalation Toxicology | Year: 2014

Perlite is a generic name for an amorphous volcanic alumina-silicate rock that expands by a factor of 4-20 when rapidly heated to 1400-1800°F (760-980°C). Both the ore and the expanded product have extensive and widespread commercial applications. Limited data on the toxicology of perlite in animal studies indicate that the LD50 (oral ingestion) is more than 10g/kg and, from a chronic inhalation study in guinea pigs and rats, that the NOAEL for the inhalation pathway is 226mg/m3. Health surveillance studies of workers in US perlite mines and expansion plants (including some workers exposed to levels greater than prevailing occupational exposure limits (OELs) conducted over 20 years indicate that the respiratory health of workers is not adversely affected. Studies in Turkish mines and expanding plants had generally similar results, but are more difficult to interpret because of high smoking rates in these populations. A recent mortality study of permanent residents of the island of Milos (Greece) exposed to various mining dusts (including perlite) resulted in non-significant increases in standard mortality ratios for pneumonia and chronic obstructive pulmonary disease (COPD), whereas a companion morbidity study revealed elevated odds ratios for allergic rhinitis, pneumonia, and COPD when compared to another industrial area of Greece. Residents were exposed to other mining dusts and other possible causes or contributing factors and no ambient monitoring data were presented so it is not possible to use this study for risk calculations of perlite-exposed populations. Perlite is regulated as a "nuisance dust" in most countries. © 2014 Informa Healthcare USA, Inc.


PubMed | ToxPath Inc.
Type: Comment | Journal: Regulatory toxicology and pharmacology : RTP | Year: 2010

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.

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