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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.

Zeiger E.,Errol Zeiger Consulting
Issues in Toxicology | Year: 2014

Cancer is a disease that is the result of a progression of cell and tissue changes leading to a tumor. In the animal, the progression of the tumor and the tissue it appears in will differ according to the specific carcinogen and the animal in which it is being tested. Not all tissues that are affected by a carcinogen develop tumors; tissue-specific and immunological factors will affect the progression and survival of the altered cells. As a consequence, no single in vitro test system will mimic the entire cancer process. When commercial organizations screen chemicals under development for potential carcinogenicity, a positive response in any one of the screening tests (usually the Ames test or a chromosome damage test) may be sufficient to remove a substance from further development. The alternative would be to perform a definitive cancer assay in the hopes that it would not be carcinogenic, and this is done only if the perceived commercial return from the chemical is substantial enough to justify the risk. Although numbers are not publically available, many chemicals are declared to be presumptive carcinogens, and not tested further in animals, based on the in silico and in vitro test results. As noted above, none of the in vitro tests measure cancer induction, but positive results in any of the tests are predictive for cancer, albeit with varying degrees of accuracy. Unfortunately, negative results in these tests are not predictive of non-carcinogenicity. Many testing schemes favored by regulatory authorities require two or three in vitro tests that measure different genetic endpoints (e.g., gene mutation; chromosome aberrations). In addition, tests that measure DNA damage (e.g., comet assay) and cell transformation are increasingly being used. One challenge associated with these multiple genotoxicity tests is that each test has its unique false positives. Therefore, as more tests are added to the battery, the proportion of both true positives and false positives will increase. If a positive response in any of the test systems is sufficient to label a substance as potential carcinogen, the use of multiple test systems could have the effect of discarding a high proportion of noncarcinogenic substances, or, alternatively lead to additional in vivo tests being performed in an attempt to distinguish the true positives from false positives. Current approaches are moving towards integrating the results of QSAR analysis, genetic toxicity tests, and tests for other precarcinogenic mechanisms (i.e., genetic recombination; cell transformation, in addition to toxicogenomics) to refine the estimation of the probability of carcinogenicity or noncarcinogenicity.

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.

Gollapudi B.B.,Dow Chemical Company | Johnson G.E.,University of Swansea | Hernandez L.G.,National Health Research Institute | Pottenger L.H.,Dow Chemical Company | And 11 more authors.
Environmental and Molecular Mutagenesis | Year: 2013

Genetic toxicology studies are required for the safety assessment of chemicals. Data from these studies have historically been interpreted in a qualitative, dichotomous "yes" or "no" manner without analysis of dose-response relationships. This article is based upon the work of an international multi-sector group that examined how quantitative dose-response relationships for in vitro and in vivo genetic toxicology data might be used to improve human risk assessment. The group examined three quantitative approaches for analyzing dose-response curves and deriving point-of-departure (POD) metrics (i.e., the no-observed-genotoxic-effect-level (NOGEL), the threshold effect level (Td), and the benchmark dose (BMD)), using data for the induction of micronuclei and gene mutations by methyl methanesulfonate or ethyl methanesulfonate in vitro and in vivo. These results suggest that the POD descriptors obtained using the different approaches are within the same order of magnitude, with more variability observed for the in vivo assays. The different approaches were found to be complementary as each has advantages and limitations. The results further indicate that the lower confidence limit of a benchmark response rate of 10% (BMDL10) could be considered a satisfactory POD when analyzing genotoxicity data using the BMD approach. The models described permit the identification of POD values that could be combined with mode of action analysis to determine whether exposure(s) below a particular level constitutes a significant human risk. Subsequent analyses will expand the number of substances and endpoints investigated, and continue to evaluate the utility of quantitative approaches for analysis of genetic toxicity dose-response data. © 2012 Wiley Periodicals, Inc.

Zeiger E.,Errol Zeiger Consulting
Environmental and Molecular Mutagenesis | Year: 2010

The currently used genetic toxicity testing battery (the Ames Salmonella test, the in vitro mammalian cell mouse lymphoma assay and/or the in vitro mammalian cell chromosome assay, and the rodent bone marrow chromosome aberration or micronucleus assay) had its origins in the early-to-mid 1970s. By the late 1970s, a large number of genetic tests had been proposed or recommended by the US-EPA for identifying germ cell mutagens and carcinogens. After a number of modifications that were primarily directed toward minimizing the number of tests used, the test battery reached its current state in the mid-1980s. This test battery, with some minor modifications in the timing or ordering of the tests is mandated by regulatory authorities worldwide. Although it would be intellectually satisfying to presume that this compendium of tests was developed and selected for regulatory screening based solely on scientific grounds, it was actually based on a combination of scientific data, theoretical considerations, chance, and advocacy, and not always in equal proportions. The evolution of the current genetic toxicity test battery, and some of the activities and considerations that directed this evolution are described. © 2010 Wiley-Liss, Inc.

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