Bentonite toxicology and epidemiology - a review.

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 critical examination of the mode of action of quinacrine in the reproductive tract in a 2-year rat cancer bioassay and its implications for human clinical use.

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.

Perlite toxicology and epidemiology--a review.

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 10 g/kg and, from a chronic inhalation study in guinea pigs and rats, that the NOAEL for the inhalation pathway is 226 mg/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.

Mode of action analysis for liver tumors from oral 1,4-dioxane exposures and evidence-based dose response assessment.

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%.

Pathology Working Group review and evaluation of proliferative lesions of mammary gland tissues in female rats fed ammonium perfluorooctanoate (APFO) in the diet for 2 years.

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.

An alternative interpretation of, "A lifetime cancer bioassay of quinacrine administered into the uterine horns of female rats".

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.

Weight-of-evidence evaluation of reproductive and developmental effects of low doses of bisphenol A.

Recent public concern has focused on potential reproductive and developmental effects from exposure to low levels of bisphenol A (BPA, CAS number 80-05-7). Two previous published reviews (Gray et al., 2004a; Goodman et al., 2006) conducted weight-of-evidence evaluations of in vivo reproductive/developmental toxicity from BPA exposure < or = 5 mg/kg-d based on studies published through February 2006. Here, an update of those analyses presents additional relevant studies that were published through July 25, 2008, and a weight-of-evidence analysis of the studies evaluated in all three reviews. As with the earlier literature, positive findings: (1) are countered by null findings in more numerous studies; (2) have not been replicated; (3) do not exhibit coherence and plausibility; (4) do not show consistency across species, doses, and time points; and/or (5) were from studies using non-oral exposure routes. Owing to the lack of first-pass metabolism, results from non-oral studies are of limited relevance to human exposure. Exposure levels in most of the low-dose oral and non-oral animal studies are generally much higher than those experienced by even the most exposed people in the general population. The weight of evidence does not support the hypothesis that low oral doses of BPA adversely affect human reproductive and developmental health.

Risk assessment due to environmental exposures to fibrous particulates associated with taconite ore.

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 review of carcinogenicity studies of asbestos and non-asbestos tremolite and other amphiboles.

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.

An updated weight of the evidence evaluation of reproductive and developmental effects of low doses of bisphenol A.

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

A tiered approach to systemic toxicity testing for agricultural chemical safety assessment.

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.

A Weight-of-evidence analysis of the cancer dose-response characteristics of 2,3,7,8-tetrachlorodibenzodioxin (TCDD).

Cancer risk assessment for TCDD and other compounds must focus on the cancer dose-response relationship and corresponding potency for the range of human doses before it can have relevance to the human exposure environment. Major differences of opinion exist over whether the dose-response curve for TCDD and other dioxin congeners is non-linear (incorporating a threshold dose region below which tumors are unlikely to be elicited) or linear (implying that any exposure has a statistical likelihood of causing cancer). The World Health Organization and others strongly support a non-linear dose-response relationship for TCDD and cancer, whereas USEPA characterizes the dose-response function as linear. This review critically summarizes the available information on TCDD dose-response relationship for cancer utilizing a weight-of-evidence approach. This assessment concludes that the available data support a non-linear dose-response relationship as being most likely and appropriate for human cancer risk assessment, i.e., the evidence suggests that a biological threshold exists in the dose-response. While proof of a threshold is not absolute, and never can be, the level of certainty for TCDD is substantial because of the concordance of many lines of evidence and the consistency of repeated observations pointing to non-linearity.