A Compendium of Mutational Signatures of Environmental Agents.

Whole-genome-sequencing (WGS) of human tumors has revealed distinct mutation patterns that hint at the causative origins of cancer. We examined mutational signatures in 324 WGS human-induced pluripotent stem cells exposed to 79 known or suspected environmental carcinogens. Forty-one yielded characteristic substitution mutational signatures. Some were similar to signatures found in human tumors. Additionally, six agents produced double-substitution signatures and eight produced indel signatures. Investigating mutation asymmetries across genome topography revealed fully functional mismatch and transcription-coupled repair pathways. DNA damage induced by environmental mutagens can be resolved by disparate repair and/or replicative pathways, resulting in an assortment of signature outcomes even for a single agent. This compendium of experimentally induced mutational signatures permits further exploration of roles of environmental agents in cancer etiology and underscores how human stem cell DNA is directly vulnerable to environmental agents. VIDEO ABSTRACT.

Prioritization of Louisiana Parishes based on Industrial Releases of Known or Suspected Carcinogens.

This investigation evaluated the geographic distribution of carcinogen releases by Louisiana industries to prioritize areas for regulatory oversight, research and monitoring, and to promote clinician awareness and vigilance. Data on estimated industry releases for the period between 1996 and 2011 were obtained from the US Environmental Protection Agency's Toxics Release Inventory. Chemicals associated with cancers of the prostate, lung, bladder, kidney, breast and non-Hodgkin lymphoma were identified. The Risk Screening Environmental Indicators model was used to derive measures or model scores based on chemical toxicity, fate and transport, and population characteristics. Parishes, chemicals, industries and media generating the highest model scores were identified. Parishes with the highest model scores were East Baton Rouge, Calcasieu, Caddo and St. John the Baptist. Clinicians should carefully monitor cancer cases in these areas, and if patients reside near or work in industry, an occupational and environmental history should be considered.

[MATline, a job-exposure matrix for the prevision of exposure to carcinogens: new functions and potential applications]. / MATline, una matrice lavorazione-esposizione per la previsione delle esposizioni a cancerogeni in Italia: nuove funzioni e potenziali utilizzi.

MATline, the job-exposure matrix for carcinogenic agents, is a data bank free accessible online. It provides data as classification and toxicological properties of carcinogenic agents, and a list of industrial processes with potential exposure to each carcinogen agent, and an up-to-date estimation of the number of activities and workers related to the industrial process on Regional basis. It also lists the target organs for which a causal relationship with the agent has been established. MATline was recently updated with the new classifications introduced by Regulation EC No. 1272/2008 (CLP). The Authorisation List or the Restriction of the Registration, Evaluation, Authorization of Chemicals (REACh) regulation specifically mark chemicals. The matrix is helpful for professionals in the public health sector to identify in advance the potential sources of exposure, and prioritise intervention plans; for occupational physicians to help identifying causes of occupational cancer cases; for health professionals in the private sector to address chemical risks; for company physicians to validate health surveillance plans; for trade unions to independently check formation contents provided to workers potentially exposed to such risks.

Evaluation of the national toxicology program report on carcinogens.

This study evaluates the National Toxicology Program's Report on Carcinogens program (RoCP) and compares it with the International Agency for Research on Cancer Monographs Program (IMP). We tracked agents classified in the RoCP since 1983 as known human carcinogens (A-List), or as reasonably anticipated to be human carcinogens (B-List). The first A-list included 24 agents, and twenty-four unique agents were added in the following 28years; twenty were listed by IMP as Group 1 (carcinogenic to humans) 7years before their A-list appearance. Group 1 also includes 30 or more agents eligible for, but not on, the A-list. The first B-list included 98 agents, and this increased to 185. Of these, 39 are in Group 2A (probably carcinogenic), and 122 are in Group 2B (possibly carcinogenic). Only 5% of the 204 agents ever on the B-list have been upgraded to the A-list. The RoCP is severely limited because it evaluates few agents and because its B-list does not distinguish between probable and possible human carcinogens. Further, it mislabels likely non-carcinogens as reasonably anticipated to be carcinogens. If the RoCP were terminated there would be no loss or delay of information available to scientific, public health and regulatory communities.

Assessment of genotoxic potential of Cr(VI) in the mouse duodenum: an in silico comparison with mutagenic and nonmutagenic carcinogens across tissues.

In vitro studies on hexavalent chromium [Cr(VI)] indicate that reduced forms of this metal can interact with DNA and cause mutations. Recently, Cr(VI) was shown to induce intestinal tumors in mice; however, Cr(VI) elicited redox changes, cytotoxicity and hyperplasia - suggesting involvement of tissue injury rather than direct mutagenesis. Moreover, toxicogenomic analyses indicated limited evidence for DNA damage responses. Herein, we extend these toxicogenomic analyses by comparing the gene expression patterns elicited by Cr(VI) with those of four mutagenic and four nonmutagenic carcinogens. To date, toxicogenomic profiles for mutagenic and nonmutagenic duodenal carcinogens do not exist, thus duodenal gene changes in mice were compared to those elicited by hepatocarcinogens. Specifically, duodenal gene changes in mice following exposure to Cr(VI) in drinking water were compared to hepatic gene changes previously identified as potentially discriminating mutagenic and nonmutagenic hepatocarcinogens. Using multivariate statistical analyses (including logistic regression classification), the Cr(VI) gene responses clustered apart from mutagenic carcinogens and closely with nonmutagenic carcinogens. These findings are consistent with other intestinal data supporting a nonmutagenic mode of action (MOA). These findings may be useful as part of a full weight of evidence MOA evaluation for Cr(VI)-induced intestinal carcinogenesis. Limitations to this analysis will also be discussed.

Quantitative characterization of the mesothelioma-inducing erionite series minerals by transmission electron microscopy and energy dispersive spectroscopy.

Air-collected erionite series minerals from Cappadocia region of Turkey were characterized quantitatively by using transmission electron microscopy (TEM) equipped with energy dispersive spectroscopy (EDS). Field emission scanning electron microscopy aided identification of fibrous minerals. Quantitative characterization guidelines for positive identification of erionites proposed by Dogan and Dogan (2008) was applied and the modified balance error formula (E%<10) and Mg-content test <0.80 were performed for each analysis. Erionite species computation showed that the mineral is erionite-K and a mean chemical formula is proposed based upon the TEM-EDS results. Among the 60 analyses, 11 passed E% test (18.3%), 33 passed Mg-content test (55.0%), and only 3 passed both E% and Mg-content tests (5.0%). This shows difficulty of quantitative characterization of the erionite series minerals. However, as erionite is the most carcinogenic mineral known and is classified by IARC as a Group-I (human) carcinogen, it requires special attention from the mineralogical community to help establish its true mineralogical properties. Quantitatively characterized erionite data are very scarce in literature. Correctly identified erionite mineral types will be useful to medical researchers in their search to find a possible cure for the deadly disease of mesothelioma.

The mutagenicity and carcinogenicity of inorganic manganese compounds: a synthesis of the evidence.

Manganese (Mn), a naturally occurring element present in many foodstuffs, is an essential trace element with many biological functions. In industry, inorganic Mn compounds have a range of different applications, although the majority of Mn is used to make alloys and steel. For the general population, the major source of exposure to Mn is dietary, although drinking water may constitute an additional source in some regions. However, in occupationally exposed humans, inhalation of Mn is likely to be an important additional route. In general, Mn and its inorganic compounds are considered to possess low mutagenic or carcinogenic potential compared with some heavy metals. In this review, an up-to-date analysis of the available published studies on the carcinogenic and genotoxic potential of inorganic Mn is provided (organic Mn compounds are not considered). The current literature indicates that Mn may be weakly mutagenic in vitro and possibly clastogenic in vivo, with unknown genotoxic effects in humans; the possible mechanisms underlying these effects are discussed. The experimental evidence on carcinogenicity (quantitative increase in incidence of thyroid tumors in mice but not rats) does not provide any clear evidence, while the available occupational and environmental epidemiological evidence is equivocal as to whether exposure to inorganic Mn is associated with a significant cancer risk. Hence, it is concluded that there is insufficient evidence to indicate that inorganic Mn exposure produces cancer in animals or humans.

Applying definitions of "asbestos" to environmental and "low-dose" exposure levels and health effects, particularly malignant mesothelioma.

Although asbestos research has been ongoing for decades, this increased knowledge has not led to consensus in many areas of the field. Two such areas of controversy include the specific definitions of asbestos, and limitations in understanding exposure-response relationships for various asbestos types and exposure levels and disease. This document reviews the current regulatory and mineralogical definitions and how variability in these definitions has led to difficulties in the discussion and comparison of both experimental laboratory and human epidemiological studies for asbestos. This review also examines the issues of exposure measurement in both animal and human studies, and discusses the impact of these issues on determination of cause for asbestos-related diseases. Limitations include the lack of detailed characterization and limited quantification of the fibers in most studies. Associated data gaps and research needs are also enumerated in this review.

The IARC october 2009 evaluation of benzene carcinogenicity was incomplete and needs to be reconsidered.

I have been familiar with the toxicological and epidemiological literature on benzene since I was a member of the NIOSH Benzene Task Force in 1975. I also am familiar with the procedures of IARC Monographs meetings from past participation, and as observer I applied this experience to the Monograph 100 F review. In October of 2009, a Working Group (WG) of the International Agency for Research on Cancer (IARC) met in Lyon, France to evaluate the available evidence for site-specific cancer to humans for 33 chemical agents and related occupations previously categorized by IARC as human carcinogens. Generally, review and discussion of the epidemiological cancer literature related to benzene was limited due to the enormous amount of material needing to be covered since the last full monograph meeting on benzene in 1981, and because 32 other chemicals and occupations were also being evaluated. Moreover, among the 33 chemicals and occupations reviewed, there was some inconsistency in the use of studies for evaluating various cancers. In some situations, consideration could have been given to the inclusion of relevant unpublished, but readily available study results. Discussion and synthesis of the animal cancer studies and mechanistic data related to specific cancers also were limited. IARC's conclusion that there is sufficient evidence for benzene to cause acute non-lymphocytic leukemia only was based on an incomplete review. IARC should schedule another monographs meeting dedicated to a complete and full review and discussion of all potential cancers related to exposure to benzene and to benzene-containing mixtures.

[Classification of substances to predict the order of magnitude of their safe water levels in terms of carcinogenic effect].

A classification has been developed to predict the safe water levels of chemical compounds in terms of their carcinogenic effect, by using as the base the LTD@10 value that is a lower 95% confidence limits for the lowest dose that statistically significantly causes a 10% increase in the incidence of cancer in laboratory animals continuously receiving a daily dose of the compound throughout their life, which is given in the CPDB internet resource, and the carcinogenicity classification adopted by the International Agency or Research on Cancer Based on an analysis ofthe maximum allowable concentration (MAC) of the standardized water substances in terms of their carcinogenic effect, the authors determined MA4 C ranges corresponding to different classes in accordance with the proposed classification. They predicted the orders of magnitude of MAC of the standardized water substances without taking into account their carcinogenic effect and those of four substances unstandardized in Russia.

Industrial-grade talc exposure and the risk of mesothelioma.

Industrial-grade talc deposits are complex mixtures of mineral particles and may vary substantially in composition across small geographical areas. Typical industrial-grade talc includes amphibole cleavage fragments, platy talc, serpentine minerals, talc in fibrous form, and a minor presence of transitional fibers. Industrial-grade talc was erroneously determined to be an asbestos-containing material due to an unintended consequence of Occupational Health and Safety Administration's (OSHA's) method for measuring airborne asbestos mandated in 1972. This error was repeated, most notably, by the National Institute for Occupational Safety and Health (NIOSH) in, 1980 for talc mined in northern New York State (NYS) by RT Vanderbilt Company (RTV). Subsequent exposure studies of northern NYS talc conducted through the, 1980s and one study published after, 2000 relied on the conclusion that talc was an asbestos-containing material to infer a causal relationship between talc and mesothelioma. The present review included (1) publications concerning talc's cancer-causing potential issued by organizations concerned with occupational and public health; (2) talc exposure studies and animal and cellular studies of RTV talc; (3) mesothelioma rates in northern NYS; and (4) mesothelioma mortality among RTV mining employees. The review indicated that failure to correctly identify the mineral characteristics of talc resulted in misleading reports concerning the carcinogenic potential of talc. However, the collective data from animal and cellular studies, mesothelioma rates in northern NYS, exposure studies, and a mortality analysis of RTV mining employees do not support a causal relationship between RTV talc and mesothelioma. This conclusion is applicable to all mineral components in RTV talc and to other industrial-grade talcs and mineral aggregates with the same components.

Preliminary risk assessment of trace metal pollution in surface water from Yangtze River in Nanjing Section, China.

In order to investigate the contamination levels of trace metals, surface water samples were collected from six regions along Yangtze River in Nanjing Section. The concentrations of trace metals (As, B, Ba, Be, Cd, Cr, Cu, Fe, Pb, Li, Mn, Mo, Ni, Sb, Se, Sn, Sr, V and Zn) were determined using inductively coupled plasma-atomic emission spectrometry (ICP-AES). Total concentrations of the metals in the water samples ranged from 825.1 to 950.4 microg/L. The result was compared with international water quality guidelines. Seven metals levels were above the permissible limit as prescribed by guidelines. A preliminary risk assessment was then carried out to determine the human health risk via calculating Hazard Quotient and carcinogenic risk of the metals. Hazard Quotients of all metals were lower than unity, except As. The carcinogenic risk of As and Cd was higher than 10(-6), suggesting that those two metals have potential adverse effects on local residents.

A stable and sensitive testing system for potential carcinogens based on DNA damage-induced gene expression in human HepG2 cell.

In order to analyze potential carcinogenic and genotoxic responses caused by exposure to pollutants existing in environment, a screening method has been established in our laboratory that uses a stably transfected HepG2 cell lines containing gadd153 promoter regions which drive a luciferase reporter gene. Activation of the exogenous gadd153 promoter was quantified using the luciferase activity following drug exposure. Twenty four agents were used to evaluate this screening assay. We selected the agents, ranging from DNA alkylating agents, oxidative agent, radiation, DNA cross-linking agent, nongenotoxic carcinogens, precarcinogenic agents, which included cadmium chloride, chromium trichloride, mercuric chloride, lead nitrate, dichloro-diphenyl-trichloroethane, deltamethrin, biphenylamine, 2-aminofluorene, benzo[a]pyrene, 2,3,7,8,-tetracblorodibenzo-p-dioxin, diethyl-stilbestrol, carbon tetrachloride, mitomycin C, hydroxycamptothecin, UV, sodium fluoride, acrylamide, hydrogen peroxide. In addition, two complex genotoxic agents (water samples) existing in the environment were selected. The results showed that all 20 tested known carcinogenic and genotoxic agents were able to induce gadd153-Luc expression at a sublethal dose. In contrast, four tested non-carcinogens, included 4-acetylaminofluorene, pyrene, benzylpenicillin sodium and vitamin C, were unable to induce gadd153-Luc expression. In conclusion, this reporter system can facilitate in vitro screening for potential carcinogens. Therefore, the gadd153-Luc test system we have developed appears to be a useful and complementary system to existing genotoxic and mutagenic tests.

The ISS Carcinogens Data Bank (BDC).

The Data Bank on Carcinogens (Banca Dati Cancerogeni, BDC) is a factual data bank, available on the Istituto Superiore di Sanità website, aimed at supporting the risk management decision making of central and local administrators. It can also represent a valuable tool for industry. The available information on carcinogenicity evaluations/classifications produced by European Union and by other institutions (IARC, USEPA, NTP, CCTN) is presented in a concise form accompanied by bibliographic references enabling the users to consult the original sources and, in some cases, to be directly connected to the relevant website. The classifications carried out by each organization in accordance with its own criteria assign the examined agents to specific qualitative categories and do not include quantitative assessment. BDC intends to provide an easy tool for experts, researchers and risk managers dealing with carcinogenic agents.

MATline: a job-exposure matrix for carcinogenic chemicals.

MATline is a tool that can be used to predict which industrial processes can be expected to involve the use of a substance that is considered carcinogenic as documented in the literature. The database includes agents carrying risk phrases R45, R49 and R40 according to the method of classification adopted by the EU and/or agents in categories 1, 2A and 2B as classified by the International Agency for Research on Cancer (IARC). Each agent is associated with a list of industrial processes coded according to the tariff headings used by the National Institute of Insurance against Occupational Injuries and Diseases (Istituto Nazionale per l'Assicurazione contro gli Infortuni sul Lavoro, INAIL). The main sources of information are the IARC Monographs and databases available through the National Library of Medicine's TOXNET portal. The matrix currently includes 600 carcinogenic agents, 23 classes of agents and some 7000 links between agents and industrial processes. MATline can be viewed on the www.dors.it website.

A review of whole animal bioassays of the carcinogenic potential of naphthalene.

This report provides a summary of deliberations conducted under the charge for members of Module A participating in the Naphthalene State-of-the-Science Symposium (NS3), Monterey, CA, October 9-12, 2006. Whole animal bioassays have been performed by the National Toxicology Program in mice and rats to ascertain the carcinogenic potential of naphthalene by inhalation exposure. A statistically significant increased incidence of pulmonary alveolar/bronchiolar adenoma (a benign lesion), was observed among female mice; an observed increase among the males did not reach statistical significance. No nasal tumors were observed in either sex. A tumorigenic response was observed in both sexes of rats, in males an increased incidence of nasal respiratory epithelium adenoma (a benign rather than malignant lesion) and in females, olfactory epithelial neuroblastoma. Interpretations of these studies vary. On the one hand, evidence of extensive non-neoplastic response in both sexes of both species indicates cytotoxicity occurred at all doses, and strongly suggests that cytotoxicity played a significant role in the tumor responses observed in the target tissues. On the other hand, olfactory epithelial neuroblastoma has rarely been observed in NTP bioassays. This review seeks to develop a consensus understanding of the scientific evidence provided by these studies, taking into account that they have been used as the basis for quantitative human cancer risk assessment, and suggests scientific studies that, if performed, could resolve scientific uncertainties.

Re-evaluation and re-classification of erionite series minerals.

Governments and industries have introduced regulatory measures requiring safety controls to limit asbestos exposure of the general public and asbestos workers. Although erionite is a more potent health hazard mineral than asbestos, it has received far less attention. Precise definition of erionite, types of these fibrous minerals, and most importantly, characterization requirements still raise questions and often lead to arguments and even legal disputes. Many bulk erionite samples used in animal and cell experiments for carcinogenicity are not mineralogically pure. To test this hypothesis, we characterized two erionite standards from Rome, Oregon, and Pine Valley, Nevada, USA. These standards were characterized quantitatively using modern analytical techniques, and one of them, the erionite standard from Rome, Oregon, passed the required tests for positive identification, but the other, the erionite standard from Pine Valley, Nevada, did not. Furthermore, we observed ambiguous definitions, incorrect identifications, and inaccurate reporting of clinical investigations. To address this problem, we established characterization guidelines for positive identification of erionite using a modified balance error formula, and we re-evaluated and re-classified published erionite data from the literature as erionite-Ca, erionite-Na, and erionite-K. If data did not pass either the E% or Mg-content test, then we propose that reference to them in the literature be disregarded. Erionite requires special attention from the mineralogical community to help establish its true carcinogenetic properties. We believe that the characterization guidelines established in this paper will contribute to setting up rules and regulations for evaluation of erionite by regulatory agencies.

Assessment of the pathogenic potential of asbestiform vs. nonasbestiform particulates (cleavage fragments) in in vitro (cell or organ culture) models and bioassays.

Asbestos fibers are highly fibrous silicate fibers that are distinguished by having a large aspect (length to diameter) ratio and are crystallized in an asbestiform habit that causes them to separate into very thin fibers or fibrils. These fibers are distinct from nonasbestiform cleavage fragments and may appear as thick, short fibers which break along cleavage planes without the high strength and flexibility of asbestiform fibers. Since cleavage fragments of respirable dimensions have generally proven nonpathogenic in animal studies, little data exists on assessing well-characterized preparations of cleavage fragments in in vitro models. The available studies show that cleavage fragments are less bioreactive and cytotoxic than asbestiform fibers.

Critical assessment of the genetic toxicity of naphthalene.

Studies demonstrating that naphthalene produces respiratory tract tumors in mice and rats raised the question of whether humans are at risk for cancer, at environmental or workplace concentrations of naphthalene. Arguments in favor of a threshold-dependent mode of action for tumor induction have been based on the facts that naphthalene does not appear to bind to DNA in vivo and that the rodent tumors occurred at high dose levels associated with substantial target site toxicity. A summary of more than 45 publications describing results for naphthalene in genetic toxicology test methods shows that 80% of the studies reported found no evidence of genotoxicity for naphthalene and that some of the studies which reported positive finding were technically unsuited to study this class of chemicals and, therefore, generated unreliable data. The remaining positive findings for naphthalene were all consistent with secondary DNA effects produced by toxicity from naphthalene alone or one of its metabolites. Based on the data reviewed in this report, it is not apparent that genetic lesions produced by naphthalene or any of its metabolites drive the tumorigenic activity.