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.
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.
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.
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.
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.
Multimorbidity is increasingly recognized as a major public health challenge of modern societies. However, knowledge about the size of the population suffering from multimorbidity and the type of ...multimorbidity is scarce. The objective of this study was to present an overview of the prevalence of multimorbidity and comorbidity of chronic diseases in the Dutch population and to explore disease clustering and common comorbidities.
We used 7 years data (2002-2008) of a large Dutch representative network of general practices (212,902 patients). Multimorbidity was defined as having two or more out of 29 chronic diseases. The prevalence of multimorbidity was calculated for the total population and by sex and age group. For 10 prevalent diseases among patients of 55 years and older (N = 52,014) logistic regressions analyses were used to study disease clustering and descriptive analyses to explore common comorbid diseases.
Multimorbidity of chronic diseases was found among 13% of the Dutch population and in 37% of those older than 55 years. Among patients over 55 years with a specific chronic disease more than two-thirds also had one or more other chronic diseases. Most disease pairs occurred more frequently than would be expected if diseases had been independent. Comorbidity was not limited to specific combinations of diseases; about 70% of those with a disease had one or more extra chronic diseases recorded which were not included in the top five of most common diseases.
Multimorbidity is common at all ages though increasing with age, with over two-thirds of those with chronic diseases and aged 55 years and older being recorded with multimorbidity. Comorbidity encompassed many different combinations of chronic diseases. Given the ageing population, multimorbidity and its consequences should be taken into account in the organization of care in order to avoid fragmented care, in medical research and healthcare policy.
Since the early 1970s, the Monographs published by the International Agency for Research on Cancer (IARC) apply rigorous procedures for the scientific review and evaluation of carcinogenic hazards. ...The Preamble to the IARC Monographs describes the objective and scope of the Monographs Programme, the scientific principles and procedures used in developing a Monograph, the types of evidence considered, and the scientific criteria that guide the evaluations. This article presents an overview of the historical development of the Preamble from the time it began to take shape in the late 1970s up to and including the most recent update in 2019. Over the years, the IARC Monographs Programme has taken account of scientific and procedural advances in identifying, reviewing, evaluating, and integrating evidence to define causes of human cancer. Since the previous edition of the Preamble in 2006, the new developments include a stronger emphasis on mechanistic evidence based on key characteristics of carcinogens; greater consideration of exposure assessment methods in epidemiological studies; and integration of the streams of evidence on cancer in humans, cancer in experimental animals, and mechanisms in reaching the overall evaluations. Thus, the Preamble now allows an evaluation process in the absence of data from animal studies, and the evidence on key characteristics of cancer may be contributed by new approach methodologies, thus potentially reducing or avoiding the use of experimental animals.
In February 2006, an IARC Monographs Working Group reevaluated the carcinogenic hazards to humans of carbon black, titanium dioxide, and talc, which belong to the group of poorly soluble, ...low-toxicity particles. The review of the relevant literature and the evaluations by the Working Group will be published in Volume 93 of the IARC Monographs series. This article summarizes the Working Group's conclusions. Epidemiological studies among workers in carbon black production and in the rubber industry provided inadequate evidence of carcinogenicity. The overall data from cancer studies in rodents exposed to carbon black provided sufficient evidence of carcinogenicity. The Working Group evaluated carbon black as possibly carcinogenic to humans, Group 2B. Reviewing the epidemiological studies in the titanium dioxide production industry, the Working Group concluded that there is inadequate evidence of carcinogenicity. Overall, the results from rodent cancer studies with titanium dioxide were considered to provide sufficient evidence. Titanium dioxide was evaluated as possibly carcinogenic to humans, Group 2B. Epidemiological studies on talc miners and millers provided inadequate evidence of carcinogenicity of inhaled talc not containing asbestos or asbestiform fibers. The evidence from rodent cancer studies was considered limited. The Working Group evaluated inhaled talc not containing asbestos or asbestiform fibers as not classifiable as to its carcinogenicity to humans, Group 3. The Working Group noted that prolonged exposure to inhaled particles at sufficiently high concentrations in experimental animals may lead to impairment of normal clearance mechanisms in the alveolar region of the lung, resulting in a continued buildup of particles that eventually leads to excessive lung burdens accompanied by chronic alveolar inflammation. The inflammatory response may give rise to increased generation of reactive oxygen species, cell injury, cell proliferation, fibrosis, induction of mutations, and, ultimately, cancer. Since many of these steps also occur in workers in dusty jobs, such as coal miners, data on cancer in animals obtained under conditions of impaired lung clearance were considered relevant to humans. In addition, impaired lung clearance in rodents exposed to ultrafine particles occurs at much lower mass concentrations than with fine particles, which adds to the human relevance.
Since the inception of the International Agency for Research on Cancer (IARC) in the early 1970s, the IARC Monographs Programme has evaluated more than 1000 agents with respect to carcinogenic ...hazard; of these, up to and including Volume 119 of the IARC Monographs, 120 agents met the criteria for classification as carcinogenic to humans (Group 1). Volume 100 of the IARC Monographs provided a review and update of Group 1 carcinogens. 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. Data on biological mechanisms of action (MOA) were extracted from the Monographs to assemble a database on the basis of ten key characteristics attributed to human carcinogens. After some grouping of similar agents, the characteristic profiles were examined for 86 Group 1 agents for which mechanistic information was available in the IARC Monographs up to and including Volume 106, based upon data derived from human in vivo, human in vitro, animal in vivo, and animal in vitro studies. The most prevalent key characteristic was "is genotoxic", followed by "alters cell proliferation, cell death, or nutrient supply" and "induces oxidative stress". Most agents exhibited several of the ten key characteristics, with an average of four characteristics per agent, a finding consistent with the notion that cancer development in humans involves multiple pathways. Information on the key characteristics was often available from multiple sources, with many agents demonstrating concordance between human and animal sources, particularly with respect to genotoxicity. Although a detailed comparison of the characteristics of different types of agents was not attempted here, the overall characteristic profiles for pharmaceutical agents and for chemical agents and related occupations appeared similar. Further in-depth analyses of this rich database of characteristics of human carcinogens are expected to provide additional insights into the MOA of human cancer development.
Overview of biological mechanisms of human carcinogens Birkett, Nicholas; Al-Zoughool, Mustafa; Bird, Michael ...
Journal of toxicology and environmental health. Part B, Critical reviews,
11/2019, Volume:
22, Issue:
7-8
Journal Article
Peer reviewed
Open access
This review summarizes the carcinogenic mechanisms for 109 Group 1 human carcinogens identified as causes of human cancer through Volume 106 of the IARC Monographs. The International Agency for ...Research on Cancer (IARC) evaluates human, experimental and mechanistic evidence on agents suspected of inducing cancer in humans, using a well-established weight of evidence approach. The monographs provide detailed mechanistic information about all carcinogens. Carcinogens with closely similar mechanisms of action (e.g. agents emitting alpha particles) were combined into groups for the review. A narrative synopsis of the mechanistic profiles for the 86 carcinogens or carcinogen groups is presented, based primarily on information in the IARC monographs, supplemented with a non-systematic review. Most carcinogens included a genotoxic mechanism.
Graphical Abstract
Graphical Abstract
Abstract
Aims
Consensus is lacking regarding the best treatment for coronary in-stent restenosis (ISR). The two most effective treatments are angioplasty with ...paclitaxel-coated balloon (PCB) and repeat stenting with drug-eluting stent (DES) but individual trials were not statistically powered for clinical endpoints, results were heterogeneous, and evidence about comparative efficacy and safety in relevant subsets was limited.
Methods and results
The Difference in Anti-restenotic Effectiveness of Drug-eluting stent and drug-coated balloon AngiopLasty for the occUrrence of coronary in-Stent restenosis (DAEDALUS) study was a comprehensive, investigator-initiated, collaborative, individual patient data meta-analysis comparing angioplasty with PCB alone vs. repeat stenting with DES alone for the treatment of coronary ISR. The protocol was registered with PROSPERO (CRD42017075007). All 10 available randomized clinical trials were included with 1976 patients enrolled, 1033 assigned to PCB and 943 to DES. At 3-year follow-up, PCB was associated with a significant increase in the risk of target lesion revascularization (TLR) compared with DES hazard ratio (HR) 1.32, 95% CI 1.02–1.70, P = 0.035; number-needed-to-harm 28.5. There was a significant interaction between treatment effect and type of restenosed stent (P = 0.029) with a more marked difference in patients with DES-ISR and comparable effects in patients with bare-metal stent-ISR. At 3-year follow-up, the primary safety endpoint of all-cause death, myocardial infarction, or target lesion thrombosis was comparable between treatments (HR 0.80, 95% CI 0.58–1.09, P = 0.152). A pre-specified subgroup analysis indicated a significant interaction between treatment effect and type of DES used to treat ISR (P = 0.033), with a lower incidence of events associated with PCB compared with first-generation DES and similar effect between PCB and second-generation DES (HR 1.06, 95% CI 0.71–1.60, P = 0.764). Long-term all-cause mortality was similar between PCB and DES (HR 0.81, 95% CI 0.53–1.22, P = 0.310); results were consistent comparing PCB and non-paclitaxel-based DES (HR 1.42, 95% CI 0.80–2.54, P = 0.235). Myocardial infarction and target lesion thrombosis were comparable between treatments.
Conclusions
In patients with coronary ISR, repeat stenting with DES is moderately more effective than angioplasty with PCB at reducing the need for TLR at 3 years. The incidence of a composite of all-cause death, myocardial infarction, or target lesion thrombosis was similar between groups. The rates of individual endpoints, including all-cause mortality, were not significantly different between groups.
In patients with coronary in-stent restenosis (ISR) requiring reintervention, it is unclear if the choice of treatment should depend on whether the restenotic stent was a bare-metal stent (BMS) or a ...drug-eluting stent (DES).
This study aimed to assess the comparative efficacy and safety of the 2 most frequently used treatments - angioplasty with drug-coated balloon (DCB) and repeat stenting DES - in patients with BMS-and DES-ISR.
The DAEDALUS (Difference in Antirestenotic Effectiveness of Drug-Eluting Stent and Drug-Coated Balloon Angioplasty for the Occurrence of Coronary In-Stent Restenosis) study was a pooled analysis of individual patient data from all 10 existing randomized clinical trials comparing DCB angioplasty with repeat DES implantation for the treatment of coronary ISR. In this pre-specified analysis, patients were stratified according to BMS- versus DES-ISR and treatment assigned. The primary efficacy endpoint was target lesion revascularization (TLR) at 3 years. The primary safety endpoint was a composite of all-cause death, myocardial infarction, or target lesion thrombosis at 3 years. Primary analysis was performed by mixed-effects Cox models accounting for the trial of origin. Secondary analyses included nonparsimonious multivariable adjustment accounting also for multiple lesions per patient and 2-stage analyses.
A total of 710 patients with BMS-ISR (722 lesions) and 1,248 with DES-ISR (1,377 lesions) were included. In patients with BMS-ISR, no significant difference between treatments was observed in terms of primary efficacy (9.2% vs. 10.2%; hazard ratio HR: 0.83; 95% confidence interval CI: 0.51 to 1.37) and safety endpoints (8.7% vs. 7.5%; HR: 1.13; 95% CI: 0.65 to 1.96); results of secondary analyses were consistent. In patients with DES-ISR, the risk of the primary efficacy endpoint was higher with DCB angioplasty than with repeat DES implantation (20.3% vs. 13.4%; HR: 1.58; 95% CI: 1.16 to 2.13), whereas the risk of the primary safety endpoint was numerically lower (9.5% vs. 13.3%; HR: 0.69; 95% CI: 0.47 to 1.00); results of secondary analyses were consistent. Regardless of the treatment used, the risk of TLR was lower in BMS- versus DES-ISR (9.7% vs. 17.0%; HR: 0.56; 95% CI: 0.42 to 0.74), whereas safety was not significantly different between ISR types.
At 3-year follow-up, DCB angioplasty and repeat stenting with DES are similarly effective and safe in the treatment of BMS-ISR, whereas DCB angioplasty is significantly less effective than repeat DES implantation in the treatment DES-ISR, and associated with a nonsignificant reduction in the primary composite safety endpoint. Overall, DES-ISR is associated with higher rates of treatment failure and similar safety compared with BMS-ISR.
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