Concordance between sites of tumor development in humans and in experimental animals for 111 agents that are carcinogenic to humans.

Since the inception of the IARC Monographs Programme in the early 1970s, this Programme has developed 119 Monograph Volumes on more than 1000 agents for which there exists some evidence of cancer risk to humans. Of these, 120 agents were found to meet the criteria for classification as carcinogenic to humans (Group 1). Volume 100 of the IARC Monographs, compiled in 2008-2009 and published in 2012, provided a review and update of the 107 Group 1 agents identified as of 2009. These agents were divided into six broad categories: (I) pharmaceuticals; (II) biological agents; (III) arsenic, metals, fibers and dusts; (IV) radiation; (V) personal habits and indoor combustions; and (VI) chemical agents and related occupations. The Group I agents reviewed in Volume 100, as well as five additional Group 1 agents defined in subsequent Volumes of the Monographs, were used to assess the degree of concordance between sites where tumors originate in humans and experimental animals including mice, rats, hamsters, dogs, and non-human primates using an anatomically based tumor nomenclature system, representing 39 tumor sites and 14 organ and tissue systems. This evaluation identified 91 Group 1 agents with sufficient evidence (82 agents) or limited evidence (9 agents) of carcinogenicity in animals. The most common tumors observed in both humans and animals were those of the respiratory system including larynx, lung, and lower respiratory tract. In humans, respiratory system tumors were noted for 31 of the 111 distinct Group 1 carcinogens identified up to and including Volume 109 of the IARC Monographs, comprising predominantly 14 chemical agents and related occupations in category VI; seven arsenic, metals, fibers, and dusts in category III, and five personal habits and indoor combustions in category V. Subsequent to respiratory system tumors, those in lymphoid and hematopoietic tissues (26 agents), the urothelium (18 agents), and the upper aerodigestive tract (16 agents) were most often seen in humans, while tumors in digestive organs (19 agents), skin (18 agents), and connective tissues (17 agents) were frequently seen in animals. Exposures to radiation, particularly X- and γ-radiation, and tobacco smoke were associated with tumors at multiple sites in humans. Although the IARC Monographs did not emphasize tumor site concordance between animals and humans, substantial concordance was detected for several organ and tissue systems, even under the stringent criteria for sufficient evidence of carcinogenicity used by IARC. Of the 60 agents for which at least one tumor site was identified in both humans and animals, 52 (87%) exhibited tumors in at least one of the same organ and tissue systems in humans and animals. It should be noted that some caution is needed in interpreting concordance at sites where sample size is particularly small. Although perfect (100%) concordance was noted for agents that induce tumors of the mesothelium, only two Group 1 agents that met the criteria for inclusion in the concordance analysis caused tumors at this site. Although the present analysis demonstrates good concordance between animals and humans for many, but not all, tumor sites, limitations of available data may result in underestimation of concordance.

A Comparison of the Efficacy of Voltage-directed Cavotricuspid Isthmus Ablation Using Mini Versus Conventional Electrodes.

Cavotricuspid isthmus (CTI) ablation is a current first-line management method for typical atrial flutter. A voltage-directed technique that systematically targets points of maximal voltage has be found to reduce procedure and fluoroscopy times without increasing recurrence. We hypothesized that this technique's efficiency would be enhanced by using signals from radial minielectrodes of a novel catheter (IntellaTip MiFi™; Boston Scientific, Natick, MA, USA). Prospectively, atrial flutter patients underwent voltage-directed ablation with a nonirrigated 8-mm-tip catheter. Ablation was either directed by conventional bipolar electrodes (group A, n = 13) or mini-electrodes (group B, n = 17) with the goal of achieving bidirectional block at the CTI and a subsequent observation time of 30 minutes. Total radiofrequency application time and lesion numbers were not significantly different. Group B had a lower mean power [38.7 watts (W) ± 2.0 W versus 44.8 W ± 1.9 W; p < 0.05] and a tendency for longer fluoroscopy and procedure times. In three of the cases in group B, a switch to an irrigated catheter was required in order to achieve bidirectional block. In group A, bidirectional block was obtained in all patients using the nonirrigated catheter with no significant increase in reconnection. Differences in the catheter performance between the two groups were driven by poorer performance of the MiFi™ catheter (Boston Scientific, Natick, MA, USA) in patients presenting in atrial flutter. Electroanatomical mapping revealed a more proximal localization of the maximal voltage by the minielectrodes as compared with the conventional bipolar electrodes, resulting in less efficient identification and ablation of the conducting muscle bundles. Final results indicated CTI ablation using minielectrodes is not superior to conventional bipolar electrodes in the use of 8-mm, nonirrigated electrodes.

Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis.

BACKGROUND: A recent review by the International Agency for Research on Cancer (IARC) updated the assessments of the > 100 agents classified as Group 1, carcinogenic to humans (IARC Monographs Volume 100, parts A-F). This exercise was complicated by the absence of a broadly accepted, systematic method for evaluating mechanistic data to support conclusions regarding human hazard from exposure to carcinogens. OBJECTIVES AND METHODS: IARC therefore convened two workshops in which an international Working Group of experts identified 10 key characteristics, one or more of which are commonly exhibited by established human carcinogens. DISCUSSION: These characteristics provide the basis for an objective approach to identifying and organizing results from pertinent mechanistic studies. The 10 characteristics are the abilities of an agent to 1) act as an electrophile either directly or after metabolic activation; 2) be genotoxic; 3) alter DNA repair or cause genomic instability; 4) induce epigenetic alterations; 5) induce oxidative stress; 6) induce chronic inflammation; 7) be immunosuppressive; 8) modulate receptor-mediated effects; 9) cause immortalization; and 10) alter cell proliferation, cell death, or nutrient supply. CONCLUSION: We describe the use of the 10 key characteristics to conduct a systematic literature search focused on relevant end points and construct a graphical representation of the identified mechanistic information. Next, we use benzene and polychlorinated biphenyls as examples to illustrate how this approach may work in practice. The approach described is similar in many respects to those currently being implemented by the U.S. EPA's Integrated Risk Information System Program and the U.S. National Toxicology Program. CITATION: Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, DeMarini DM, Caldwell JC, Kavlock RJ, Lambert P, Hecht SS, Bucher JR, Stewart BW, Baan R, Cogliano VJ, Straif K. 2016. Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 124:713-721; http://dx.doi.org/10.1289/ehp.1509912.

Scientific considerations for evaluating cancer bioassays conducted by the Ramazzini Institute.

BACKGROUND: The Ramazzini Institute (RI) has completed nearly 400 cancer bioassays on > 200 compounds. The European Food Safety Authority (EFSA) and others have suggested that study design and protocol differences between the RI and other laboratories by may contribute to controversy regarding cancer hazard findings, principally findings on lymphoma/leukemia diagnoses. OBJECTIVE: We aimed to evaluate RI study design, protocol differences, and accuracy of tumor diagnoses for their impact on carcinogenic hazard characterization. METHODS: We analyzed the findings from a recent Pathology Working Group (PWG) review of RI procedures and tumor diagnoses, evaluated consistency of RI and other laboratory findings for chemicals identified by the RI as positive for lymphoma/leukemia, and examined evidence for a number of other issues raised regarding RI bioassays. The RI cancer bioassay design and protocols were evaluated in the context of relevant risk assessment guidance from international authorities. DISCUSSION: Although the PWG identified close agreement with RI diagnoses for most tumor types, it did not find close agreement for lymphoma/leukemia of the respiratory tract or for neoplasms of the inner ear and cranium. Here we discuss a) the implications of the PWG findings, particularly lymphoma diagnostic issues; b) differences between RI studies and those from other laboratories that are relevant to evaluating RI cancer bioassays; and c) future work that may help resolve some concerns. CONCLUSIONS: We concluded that a) issues related to respiratory tract infections have complicated diagnoses at that site (i.e., lymphoma/leukemia), as well as for neoplasms of the inner ear and cranium, and b) there is consistency and value in RI studies for identification of other chemical-related neoplasia.

The link in Linking.

We present 2 cases of the slow-fast form of AVNRT with initially narrow QRS complexes followed by sudden unexpected transition to persistently wide QRS complexes due to aberrant intraventricular conduction. Introduction of a properly timed extrastimulus in one case and critical oscillations in cycle length due to short-long coupling in the second case set the stage for the initial bundle branch block. However, persistence of the aberrancy pattern once the initial event abated was maintained by the "linking" phenomenon. Delayed, retrograde concealed activation from the contralateral bundle branch perpetuated the initial bundle branch block.

Human health effects of trichloroethylene: key findings and scientific issues.

BACKGROUND: In support of the Integrated Risk Information System (IRIS), the U.S. Environmental Protection Agency (EPA) completed a toxicological review of trichloroethylene (TCE) in September 2011, which was the result of an effort spanning > 20 years. OBJECTIVES: We summarized the key findings and scientific issues regarding the human health effects of TCE in the U.S. EPA's toxicological review. METHODS: In this assessment we synthesized and characterized thousands of epidemiologic, experimental animal, and mechanistic studies, and addressed several key scientific issues through modeling of TCE toxicokinetics, meta-analyses of epidemiologic studies, and analyses of mechanistic data. DISCUSSION: Toxicokinetic modeling aided in characterizing the toxicological role of the complex metabolism and multiple metabolites of TCE. Meta-analyses of the epidemiologic data strongly supported the conclusions that TCE causes kidney cancer in humans and that TCE may also cause liver cancer and non-Hodgkin lymphoma. Mechanistic analyses support a key role for mutagenicity in TCE-induced kidney carcinogenicity. Recent evidence from studies in both humans and experimental animals point to the involvement of TCE exposure in autoimmune disease and hypersensitivity. Recent avian and in vitro mechanistic studies provided biological plausibility that TCE plays a role in developmental cardiac toxicity, the subject of substantial debate due to mixed results from epidemiologic and rodent studies. CONCLUSIONS: TCE is carcinogenic to humans by all routes of exposure and poses a potential human health hazard for noncancer toxicity to the central nervous system, kidney, liver, immune system, male reproductive system, and the developing embryo/fetus.

Cutting Edge PBPK Models and Analyses: Providing the Basis for Future Modeling Efforts and Bridges to Emerging Toxicology Paradigms.

Physiologically based Pharmacokinetic (PBPK) models are used for predictions of internal or target dose from environmental and pharmacologic chemical exposures. Their use in human risk assessment is dependent on the nature of databases (animal or human) used to develop and test them, and includes extrapolations across species, experimental paradigms, and determination of variability of response within human populations. Integration of state-of-the science PBPK modeling with emerging computational toxicology models is critical for extrapolation between in vitro exposures, in vivo physiologic exposure, whole organism responses, and long-term health outcomes. This special issue contains papers that can provide the basis for future modeling efforts and provide bridges to emerging toxicology paradigms. In this overview paper, we present an overview of the field and introduction for these papers that includes discussions of model development, best practices, risk-assessment applications of PBPK models, and limitations and bridges of modeling approaches for future applications. Specifically, issues addressed include: (a) increased understanding of human variability of pharmacokinetics and pharmacodynamics in the population, (b) exploration of mode of action hypotheses (MOA), (c) application of biological modeling in the risk assessment of individual chemicals and chemical mixtures, and (d) identification and discussion of uncertainties in the modeling process.

Amplitude Changes during Ventricular Fibrillation: A Mechanistic Insight.

INTRODUCTION: Clinically in ventricular fibrillation (VF), ECG amplitude, and frequency decrease as ischemia progresses and predict defibrillation success. In vitro ECG amplitude declines without ischemia, independent of VF frequencies. This study examines the contribution of cellular electrical activity and global organization to ECG amplitude changes during VF. METHODS AND RESULTS: Rabbit hearts were Langendorff-perfused (40 mL/min, Tyrode's solution) and loaded with RH237. During VF, ECG, and epicardial optical action potentials were recorded (photodiode array; 256 sites, 15 mm × 15 mm). After 60 s of VF, perfusion was either maintained, global ischemia produced by low-flow (6 mL/min), or solution [K(+)](o) raised to 8 mM. Peak-to-peak amplitude was determined for all signals. During VF, in control, ECG amplitude decreased to a steady-state (∼57% baseline), whereas in low-flow steady-state was not reached with the amplitude continuing to fall to 33% of baseline by 600 s. Optically, LV amplitude declined more than RV, reaching significance in control (LV vs. RV; 33 ± 5 vs. 63 ± 8%, p < 0.01). During VF in 8 mM [K(+)](o), amplitude changes were more complex; ECG amplitude increased with time (105 ± 13%), whilst LV amplitude decreased (60 ± 15%, p < 0.001). Microelectrode studies showed amplitude reduction in control and 8 mM [K(+)](o) (to ∼79 and ∼93% baseline, respectively). Evaluation of electrical coordination by cross-correlation of optical signals showed as VF progressed coordination reduced in control (baseline 0.36 ± 0.02 to 0.28 ± 0.003, p < 0.01), maintained in low-flow (0.41 ± 0.03 to 0.37 ± 0.005, p = NS) and increased in 8 mM [K(+)](o) (0.36 ± 0.02 to 0.53 ± 0.08, p < 0.05). CONCLUSION: ECG amplitude decline in VF is due to a combination of decreased systolic activation at the cellular level and increased desynchronization of inter-cellular electrical activity.

DEHP: genotoxicity and potential carcinogenic mechanisms-a review.

Di(ethylhexyl) phthalate (DEHP) is a manufactured chemical commonly added to plastics: it is a ubiquitous environmental contaminant to which humans are exposed through multiple routes. DEHP is a rodent carcinogen with an extensive data base on genotoxicity and related effects spanning several decades. Although DEHP has been reported to be negative in most non-mammalian in vitro mutation assays, most studies were performed under conditions of concurrent cytotoxicity, precipitation, or irrelevant metabolic activation. However, a number of in vitro rodent tissue assays have reported DEHP to be positive for effects on chromosomes, spindle, and mitosis. A robust database shows that DEHP increases transformation and inhibits apoptosis in Syrian hamster embryo cells. In a transgenic mouse assay, in vivo DEHP exposure increased the mutation frequency only in the liver, which is the target organ for cancer. In vitro exposure of human cells or tissues to DEHP induced DNA damage; altered mitotic rate, apoptosis, and cell proliferation; increased proliferation, tumor mobility, and invasiveness of tumor cell lines; and activated a number of nuclear receptors. DEHP has been shown to be an agonist for CAR2, a novel constitutive androstane receptor occurring only in humans. Environmental exposures of humans to DEHP have been associated with DNA damage. After taking into account study context and relevant issues affecting interpretation, in vitro studies reported that a similar DEHP concentration range induced both mutagenic and non-mutagenic effects in human tissues and, using a much more limited rodent database, transformation of embryonic rodent tissues. The human and rodent data suggest that DEHP induces cancer through multiple molecular signals, including DNA damage. The analyses presented here may provide guidance for similar data sets used in structure-activity relationships, computational-toxicology extrapolations, and attempts to extrapolate in vitro results to predict in vivo effects for hazard characterization.

Simplified electrocardiogram sampling maintains high diagnostic capability for atrial fibrillation: implications for opportunistic atrial fibrillation screening in primary care.

AIMS: Atrial fibrillation (AF) is a major cause of morbidity, mortality, and health resource consumption. However, as many patients with chronic AF are asymptomatic, rapid, accurate opportunistic screening is needed in primary care to detect AF. Conventional electrocardiogram (ECG) technology is too clumsy and time consuming for mass opportunistic screening, thus technology that allows easy, rapid, yet accurate AF screening is required. To address this requirement a prototype hand-held electrode assembly was developed. We hypothesized that a 6-lead frontal-plane ECG acquired from this apparatus in a seated, clothed patient would be as accurate at detecting AF as conventional 12-lead ECG in the undressed, supine patient (the 'gold standard'). METHODS AND RESULTS: Electrocardiograms were obtained from 78 patients with AF and 79 with sinus rhythm (SR). All had a conventional 12-lead ECG, a 6-lead ECG from conventionally positioned limb electrodes, a supine 6-lead recording using the prototype recorder placed on the lower thorax/upper abdomen, and a 6-lead prototype recording in the seated patient, the latter with loosened clothing only. Electrocardiograms were randomly and blindly assessed by two cardiologists for (i) diagnosis of AF vs. SR and (ii) tracing quality (subjectively assessed as good, adequate, or bad). Compared with conventional 12-lead ECG recordings, all 'new' recording methods performed satisfactorily with sensitivities ≥90% (90-99%), specificities ≥94% (94-100%), positive predictive values ≥94% (94-100%), negative predictive values ≥90% (90-99%), and accuracies ≥93% (93-99%). Tracing quality was higher in conventional 12-lead recordings (71 and 80% were assessed as good by the two observers) compared with conventional 6-lead (57 and 59%), supine prototype (41 and 31%), and sitting prototype (39 and 19%). CONCLUSIONS: Despite inferior electrocardiographic quality a 6-lead frontal plane ECG acquired by a simple prototype hand-held electrode assembly allowed reliable differentiation of AF from SR compared with standard 12-lead ECG.

Ventricular fibrillation following successful DC cardioversion for atrial fibrillation.

Cardioversion remains an important therapy in the management of atrial fibrillation. Here, we report a case where direct current cardioversion resulted in a sudden dramatic change of heart rate that was associated with multiple ventricular fibrillation arrests in a manner akin to that previously observed post-atrioventricular node ablation.

Slowing of Electrical Activity in Ventricular Fibrillation is Not Associated with Increased Defibrillation Energies in the Isolated Rabbit Heart.

Prolonged out-of-hospital ventricular fibrillation (VF) arrests are associated with reduced ECG dominant frequency (DF) and diminished defibrillation success. Partial reversal of ischemia increases ECG DF and improves defibrillation outcome. We have investigated the metabolic components of ischemia responsible for the decline in ECG DF and defibrillation success. Isolated Langendorff-perfused rabbit hearts were loaded with the voltage-sensitive dye RH237. Using a photodiode array, epicardial membrane potentials were recorded at 252 sites (15 mm × 15 mm) on the anterior surface of the left and right ventricles. Simultaneously, a global ECG was recorded. VF was induced by burst pacing, and after 60s, perfusion was either reduced to 6 ml/min or the perfusate composition changed to impose hypoxia (95% N(2)/5% CO(2)), pH 6.7 (80% O(2)/20% CO(2)), or hyperkalemia (8 mM). Using fast Fourier transform, power spectra were created from the optical signals and the global ECG. The optical power spectra were summated to give a global power spectrum (pseudoECG). At 600 s the minimum defibrillation voltage (MDV) was determined by step-up protocol. During VF, the ECG and pseudoECG DF were reduced by low-flow ischemia (9.0 ± 1.0 Hz, p < 0.01, n = 5) and raised [K(+)](o) (12.2 ± 1.3 Hz, p < 0.05, n = 7) compared to control (19.2 ± 1.5 Hz, n = 20), but were unaffected by acidic pH(o) (16.7 ± 1.1 Hz, n = 11) and hypoxia (14.0 ± 1.2 Hz, n = 10). In contrast, the MDV was raised by acidic pH (156.1 ± 26.4 V, p < 0.001) and hypoxia (154.1 ± 22.1 V, p < 0.01) compared to control (65.6 ± 2.3 V), but comparable changes were not observed in low-flow ischemia (61.0 ± 0.5 V) or raised [K(+)](o) (56 ± 3 V). In summary, different metabolites are responsible for the reduction in DF and the increase in defibrillation energy during ischemic VF.

Research recommendations for selected IARC-classified agents.

OBJECTIVES: There are some common occupational agents and exposure circumstances for which evidence of carcinogenicity is substantial but not yet conclusive for humans. Our objectives were to identify research gaps and needs for 20 agents prioritized for review based on evidence of widespread human exposures and potential carcinogenicity in animals or humans. DATA SOURCES: For each chemical agent (or category of agents), a systematic review was conducted of new data published since the most recent pertinent International Agency for Research on Cancer (IARC) Monograph meeting on that agent. DATA EXTRACTION: Reviewers were charged with identifying data gaps and general and specific approaches to address them, focusing on research that would be important in resolving classification uncertainties. An expert meeting brought reviewers together to discuss each agent and the identified data gaps and approaches. DATA SYNTHESIS: Several overarching issues were identified that pertained to multiple agents; these included the importance of recognizing that carcinogenic agents can act through multiple toxicity pathways and mechanisms, including epigenetic mechanisms, oxidative stress, and immuno- and hormonal modulation. CONCLUSIONS: Studies in occupational populations provide important opportunities to understand the mechanisms through which exogenous agents cause cancer and intervene to prevent human exposure and/or prevent or detect cancer among those already exposed. Scientific developments are likely to increase the challenges and complexities of carcinogen testing and evaluation in the future, and epidemiologic studies will be particularly critical to inform carcinogen classification and risk assessment processes.

Right coronary artery damage during cavotricuspid isthmus ablation.

Radiofrequency ablation of the cavotricuspid isthmus is the first-line treatment for typical atrial flutter. Despite the close proximity of the right coronary artery (RCA) to the cavotricuspid isthmus, only four cases of arterial injury have been reported during radiofrequency ablation, all detected postablation by inferior ST elevation. Here, we report atrioventricular (AV) conduction delay during coronary sinus pacing as a possible early sign of RCA involvement and review the previous literature on RCA damage and variations of AV nodal circulation.