Aldehydes such as formaldehyde and acetaldehyde are commonly present in our daily life from smoking. Other carcinogens present in cigarette smoke are vinyl chloride, and ethylene oxide [ 12 , 13 ]. Cigarette smoke also contains oxidants such as nitric oxide and free radicals that are involved in oxidative damage produced by cigarette smoke. Cigarette smoke contains diverse carcinogens. PAH, N-nitrosamines, aromatic amines, 1,3-butadiene, benzene, aldehydes, and ethylene oxide are among the most important carcinogenic compounds present in cigarette smoke [ 12 ].
Polycyclic aromatic hydrocarbons PAHs are a group of organic compounds composed of two or more fused aromatic benzene rings containing only carbon and hydrogen atoms. PAHs containing two and three rings are present in vapor phase in atmosphere as they have low molecular weight. However, PAHs with five rings or more are largely bound to particles and considered the most hazardous to humans. PAHs with intermediate molecular weight four rings are allocated between vapor and particulate phases.
More than 11 carcinogenic PAHs were detected in the air of industrial countries. The most widely-spread PAHs compound is benzo[a]pyrene which is used as a marker for total exposure to carcinogenic PAHs. Polycyclic hydrocarbons differ in their carcinogenicity; some have weak carcinogenic effect like, the compound dibenzo[a,c]anthracene, while others have potent carcinogenicity like 3-methylcholanthrene and 7,dimethylbenzo[a]anthracene [ 14 ].
PAHs are released into the environment form the combustion of carbon containing materials at high temperature. Indoor air contamination by PAHs occurs from indoor emission sources such as smoking, cooking, domestic heating with fuel stoves and open fireplaces, as well as from intrusion of outdoor air [ 14 ]. PAHs emissions from motor vehicle, power generation plants, waste incinerators and open burning are considered the main component of outdoor sources in industrialized countries.
In developing countries, cooking and heating with solid fuels such as wood, agricultural residues or coal remains the main contributing source of indoor PAHs air pollution [ 14 ]. Individual exposure to PAHs occurs via inhalation of air, consumption of food and water, and dermal contact with soil and dust.
PAHs are easily absorbed from the gastrointestinal tract of human, as they are highly lipid soluble. Then they are rapidly distributed in a various tissues with a tendency for localization in fatty tissues. PAHs metabolized via the cytochrome Ps and epoxide hydrolase enzymes [ 14 ].
The carcinogenic potential of PAHs has been well established for decades, and evidence to date has resulted in many of these compounds being labeled as reasonably carcinogenic. Lung tumors have been detected in animals exposed to PAHs. In vitro studies showed that c-myc expression, adduct formation, and cell-cycle progression are altered in lung epithelial cells exposed to PAHs [ 15 ].
The mechanisms of carcinogenesis of PAHs have been extensively investigated. Recent studies indicate that PAHs can alter cell signaling cascades that control cell communication, growth, and immune functions.
PAHs have been shown to act through nuclear receptors [ 15 ]. For example dimethylnitrosamine causes liver cancer, whereas some of the tobacco specific nitrosamines cause lung cancer.
Nitrates and nitrites occur naturally in fruit and vegetables, which are considered as an important part of a healthy diet in most countries. Nitrates and nitrites are often used as food additives in processed meats such as ham, bacon, sausages and hot dogs to prevent toxin production by Clostridium Botulinum the microorganism responsible for botulism , and preserve meat products recognizable appearance and flavor as well [ 13 ]. Nitrosamines are produced by chemical reactions of nitrates or its reduced form nitrites with amines in the meat during its processing, storage, and cooking.
N - nitrosodimethylamine NDMA is one of the most frequently occurring nitrosamines in our dietary foods. NDMA is a potent carcinogen, associated with increased risk of malignant tumors of liver, lung, and stomach [ 13 ]. Nitrates NO 3 and nitrites NO 2 are inorganic compounds, composed of a single nitrogen atom N and a number of oxygen atoms O. It is believed that nitrates themselves are relatively inert, and activated by nitrate reductase enzyme from bacteria in the mouth into to nitrites.
Then nitrites are converted to nitrous acid by the acidic juices in stomach, which further reacts with amines to form nitrosamines. The carcinogenesis of nitrosamines could be through gene mutation and DNA adductions.
Aflatoxin is a potent human carcinogen. It is a naturally occurring toxic metabolite produced by certain fungi Aspergillus flavis. Aflatoxins are an interesting example of DNA damaging agents from a natural source. Among the aflatoxins of natural origin, aflatoxin B1 is the most potent hepatocarcinogen and considered to be the most toxic. Aflatoxins are regularly found in improperly stored staple commodities such as cassava, corn, cotton seed, millet, peanuts, rice, sesame seeds, and wheat [ 16 ].
Aflatoxins may be metabolized in the liver to a reactive epoxide intermediate or hydroxylated to become the less harmful aflatoxin M 1. Aflatoxins are commonly ingested through contaminated food. Animals fed contaminated food can pass aflatoxin transformation products into eggs, milk products, and meat.
However the most toxic type of aflatoxin B 1 , can permeate through the skin. It has been suggested that aflatoxins induce p53 gene mutations in hepatocytes [ 16 ].
Many drugs have carcinogenic potential such as intercalating antibiotics or nitroimidazole derivatives like metronidazole. The mechanism of action of nitroimidazoles is through reduction of the nitro group in predominantly anaerobic environments leads to formation of reactive intermediate products and hence destruction of DNA strands. Antimicrobial agents can be directly toxic, can interact with other drugs to increase their toxicity, or can alter microbial flora to cause infection by organisms that are normally saprophytic [ 17 ].
The majority of cytostatic agents like: melphalan, nitrosourea, etoposide are potentially carcinogenic. Certain tumors have been triggered by chemotherapy.
Furthermore, some cytostatic agents have an immunosuppressive effect which renders the organism unable to eliminate mutated cells efficiently. Owing to increased survival rates after chemotherapy, some patients develop years after primary therapy secondary malignancy. Most of secondary malignancies appear in the first 10 years after chemotherapy, especially after alkylating agents or nitrosourea derivatives.
According to previous studies, alkylating agents such as cyclophosphamide, melphalan or procarbazine have the strongest leukemogenic potential [ 18 ].
Pesticides are a group of biologically active natural and synthetic chemicals, which are used to kill unwanted harmful insects, fungi, rodents and plants. All pesticides contain biologically active compounds that are purposely designed to interfere with normal biologic processes in target organisms. Therefore, individuals exposed to certain pesticides may be at risk to the development of certain cancers. Exposure to these pesticides could be through occupational exposures, the ingestion of contaminated food and water, by absorption through the skin, or by inhalation during application [ 19 ].
European and Global cancer incidence and mortality figures. Data are reported as estimated number of incident cases and deaths for all cancers both sexes, all ages. Data refer to year In parenthesis, estimated prevalence 5-year survival from first diagnosis.
In Europe, cancer is the most frequently occurring form of non-communicable disease and the second most common cause of death, after cardiovascular diseases. Estimates for indicate 4. This is in spite of major improvements in diagnosis and therapy, and a slight decrease in deaths linked to certain cancers. A number of interrelated causes contribute to the high cancer incidence in Europe. In particular, these include: 1 lifestyles typical of industrialised countries high very high HDI Colditz and Wei, ; Landrigan et al.
Occurrence and survival data show significant disparities in tumour types across European countries; these can be linked to differences in environmental and occupational exposure, including air pollution level differences, lifestyles, demographic factors and to some extent to the budget that national governments devote to health care Arnold et al.
At international level, the World Health Organization WHO has recognised the burden of cancer on health and the resulting social and economic impacts. Acknowledging the important contribution that effective chemical safety assessment has to inform risk management measures and reduce the burden of cancer, we reflect here on the role of carcinogenicity assessment in the broader public health context.
We take into consideration actual cancer scenarios, the contribution of chemical exposure to the disease, the impact of current EU legislative measures, and the influence of public health policies. In addition, we report on current scientific advances in carcinogenicity assessment and their potential to help the fight against cancer. Cancer is a broad term encompassing many different highly heterogeneous but related diseases affecting potentially almost every tissue in the body NIH NCI, While different explanations have been put forward for the causes and mechanisms of cancer, it is acknowledged that there is a complex interplay of multiple risk factors, which can contribute at the same time or at different stages over longer time frames Anand et al.
From an evolutionary perspective, cancer can be regarded as a conserved trait across species, typically the result of an adaptive response to rapid changes in the environment Aktipis and Nesse, From this perspective, the ecological context of cancer cells parallels that of the organisms they live in.
They respond similarly to: the emergence of new stressors; to increased availability of nutrients; to the allocation of energy to growth at the expense of survival as reproduction at the expense of health ; to cellular defence mechanisms e.
While cancers cannot be completely avoided, evidence strongly suggests that susceptibility to the disease can be reduced significantly by reducing the impact of several risk factors. Cancer risk factors that might be largely preventable include biological agents infections , exposure to synthetic chemicals through work or consumer products, and lifestyle factors such as exposure to sunlight, poor diet, being overweight, tobacco use and consumption of alcohol.
While the specific contribution from chemicals to cancer is difficult to quantify with certainty, a number of estimates have been made. In , Anand and colleagues Anand et al. Family history and ageing represent instead unavoidable risk factors. With increasing age, stress resistance decreases as well as the ability to repair cellular and DNA damage.
Since this is combined with the cumulative use of pharmaceuticals and exposure to stressors, including chemicals, the vulnerability to cancer might increase with age. For some types of cancer, such as oesophageal carcinoma, liver hepatocellular carcinoma, pancreatic adenocarcinoma, pheochromocytoma, stomach adenocarcinoma, bladder and colon cancers, the effect of ageing has been suggested to outweigh other risk factors Podolskiy and Gladyshev, Despite the high heterogeneity of cancer types, humans are mainly afflicted by breast, prostate, lung and colorectal cancer.
There are also increasing trends in cancers of the stomach, cervix, liver and bladder Rahib et al. In Europe, breast cancer is the most common, with nearly half a million new cases per year.
Prostate cancer has shown a levelling-off in its mortality rate which is most likely due to the introduction of early screening for the prostate-specific antigen PSA biomarker Fig. Estimated incidence by cancer site in EU in The chart reports the estimated percentage distribution of cancers in the EU 28 Member States for the year , both sexes, all ages. Each bar is proportional to the contribution of each cancer to the total.
The prevalence of these four cancers is not attributable to a single cause although they share some common traits. Notably, these cancers have similar anatomical origin. In fact, their cells derive from the same original epithelial cell type same original germ layer. Since epithelia lie at the interface between the organism and its environment, they are the first to respond to any type of insult.
Such responses occur in a multi-step process and may lead to chronic inflammatory pathologies and cancer formation, as observed in the case of colorectal cancer in the gastrointestinal tract Madia et al. Although the anatomical origin can influence tumour classification and development, similarities in mutations and signalling pathways have been observed. These have been linked to family history or specific mutations as in the case of BRCA prostate and breast cancers Agalliu et al.
Furthermore, compelling evidence has recently linked breast, prostate and colorectal cancers with insulin resistance. This is a pathologic condition observed in metabolic disorders such as obesity and type-2 diabetes mellitus and associated immune deregulation to which both genetic and environmental factors might jointly contribute.
The environmental factors likely reflect the shift toward unhealthy dietary habits typical of industrialised countries, including overeating and consumption of processed food or excessive amounts of nutrient supplements, hormones and growth factors.
In addition, exposure to contaminants in the food chain may play a role Arcidiacono et al. The prevalence of lung cancer is attributable mainly to occupational exposures but also to air pollution and tobacco use. A higher risk of lung cancer has also been associated with chronic pulmonary diseases Tu et al. Scientific research has led to considerable insights into the many ways exogenous chemicals can adversely affect human health and cause cancer.
However, accurately estimating the proportion of all cancer risk attributable to chemical exposure remains a formidable challenge. There are many variables to take into account, including duration of exposure, demography, geography, environment, and individual susceptibility.
Differences in estimates can be due to study context target cancer or target pollutant or to uncertainties in the collection of data or because of different approaches to data analysis. Moreover, as recently discussed at a Scientific Committee Seminar organized by the European Environmental Agency, there has been an overall underestimation of the potential risk of environmental chemicals, the majority of which are less studied.
It has been reported in fact that there has been a historical bias toward deepening knowledge and providing more information on chemicals with known risk EEA Chemicals for a sustainable future, The strongest evidence for cancer occurrence associated with chemical exposure is related to occupational settings.
In the workplace, characterisation of the environment, exposure levels, exposure time-frame and the health status of workers can be tracked in a precise and accurate way.
This suggests that a significant number of chemicals are still in need of thorough review, implying a considerable demand for testing and evaluation of carcinogenic potential.
In this regard, the legislative system in place for registration and authorisation through REACH EC Regulation , , and classification and labelling through the CLP Regulation EC Regulation , , has contributed to the identification and management of the risks linked to the substances manufactured and marketed in the EU. In addition, several other pieces of EU legislation including those regulating biocides, pesticides, drinking water, and occupational safety and health OSH have all contributed to the stricter control of carcinogenic substances.
Chemical production volumes in the EU. Percent variation of aggregated production volumes, in million tons, of chemicals over years — in the EU. Chemicals were broken down into five toxicity classes and non-hazardous chemicals: carcinogenic, mutagenic and toxic to reproduction CMR chemicals; chronic toxic chemicals; very toxic chemicals; toxic chemicals; harmful chemicals and non-hazardous.
These classes are derived from the risk phrases assigned to individual substances in Annex 6 of the Dangerous Substances Directive amended in , and adapted to the CLP most recent classification EU Report, Substances classified as carcinogens.
Data retrieved from the CLP inventory. The inventory contains classification and labelling information on notified and registered substances received from manufacturers and importers but it also includes the list of harmonised classifications. This reduction may be partly explained by the increase of chemicals identified as substances of very high concern CMRs; Persistent, Bioaccumulative and Toxic substances - PBTs; very Persistent or very Bioaccumulative - vPvB and classified as requiring either specific authorisation or restriction measures on marketing and use Article 59 10 EC Regulation , A number of different health indicators are used to estimate the positive impact of chemical risk management such as reduced mortality, increased survival rates, reduction in direct and indirect medical costs and increases in worker productivity.
In relation to 13 well known carcinogens for example, it is estimated that over 1 million deaths from cancer have been avoided EU Study, The assessment of the impact of EU chemicals legislation on environmental exposure of the general public has been limited by uncertainties related to data collection, health indicators and confounding factors.
In addition, it is very difficult to describe the causal relationship between environmental chemicals and cancer disease EU Report, ; EU Study, The assessments conducted also confirmed the need for more initiatives to generate information and facilitate understanding e. Specific associations between chemical exposures and certain cancers have been recently reported. For example, breast cancer has been associated with the cumulative exposure to pesticides and other chemicals Jeon et al.
Several key studies have been reviewed, suggesting higher breast cancer risk for exposures during breast development to dichlorodiphenyltrichloroethane DDT , dioxins, perfluorooctanesulfonamide PFOSA and air pollutants and, for occupational exposure, to solvents and other mammary carcinogens such as gasoline Rodgers et al. To focus on one particular case in , an eight-year-old Chinese girl was recognised as the youngest person to get lung cancer due to fine particulate matter via outdoor air pollution Kessler, , declared as carcinogenic to humans by IARC IARC, Concerns have also been reported concerning chronic, low-level exposure to chemical mixtures, which are considered to be poorly characterised and yet to be systematically addressed Goodson et al.
Notably, in recent years the European Commission, acknowledging that the assessment and management of mixtures is only partly covered by current legislation, has identified several gaps and areas for action.
A number of initiatives both at research and policy level are on-going, which are expected to have a strong impact EC Communication, ; Bopp et al.
Ongoing dialogue between the Commission services, European agencies and scientific experts is focused on reviewing the current state of knowledge and further elaborating and prioritising policy and research needs Bopp et al. While some information on the effects of chemicals during critical windows of susceptibility e. Thus, effects undetected during those specific windows of exposure might still give concern for delayed effects leading to cancer later in life such as for endocrine-disrupting chemicals or neuro- or immuno-developmental toxic chemicals Biro and Deardorff, ; Grandjean and Bellanger, ; Hughes and Waters, ; Osborne et al.
Moreover, individual substances can independently trigger several of the mechanisms of the carcinogenic process EEA Chemicals for a sustainable future, ; Kienzler et al. Recent discussions suggest that the REACH Legislation, while contributing to reducing the overall risks of chemicals in the environment, is protecting mainly against highly toxic chemicals in the workplace, and inadvertently encouraging the introduction of new substances with unknown properties EEA Chemicals for a sustainable future, ; Scheringer, Indeed, chemical exposure scenarios are changing quite rapidly both in terms of the amount and diversity of substances Hendry et al.
Changes in toxicological properties of chemicals and exposure patterns are predicted to adversely affect both human health and the environment EEA, With regard to carcinogens, the proportion of non-genotoxic versus genotoxic carcinogens in the environment is expected to increase, since scientific knowledge on DNA reactivity allows industrial chemists to design compounds without overly reactive moieties.
In addition, the manufacture and use of novel types of substances including nanomaterials, new generation pesticides and pharmaceuticals e. This raises new challenges for risk assessment and risk management.
Testing procedures and regulatory information requirements will have to be revisited and gaps eventually filled. Several groups have long questioned standard regulatory testing procedures which mainly rely on rodent assays Table 1 , pointing out a number of drawbacks related to their applicability to assess the potential of chemicals to cause cancer in humans Heinonen et al. Internationally agreed testing methods for carcinogenicity. Data were retrieved from the OECD website.
The above methods are used by industry and governments for the regulatory safety testing of carcinogenic potential of chemicals. Scientific concerns include the overestimation of carcinogenic effects due to the typically high doses used in rodent studies and the uncertainties linked to extrapolation from rodent to humans due to species-specific biology and chemical mode of action Cohen, ; Goodman, ; Madia et al. Importantly too, the 2-year rodent bioassay and chronic toxicity studies do not specifically address the four cancers of most concern described above since they were originally designed to cover a very wide range of possible health effects and cancer types.
In addition, the 2-year rodent bioassay has proven inadequate to specifically predict hormonally induced reproductive tumours Thayer and Foster, For some types of tumours such as prostate, no adequate animal model exists. In addition, for tumours in the ovary, the human tumours derive from different cellular origins than those induced by chemicals in rodents. In breast cancer, it has been reported that mammary gland premalignant lesions in mice do not parallel human pathological changes Thayer and Foster, Coupled with all these concerns over the scientific relevance of the animal tests for carcinogenicity, is the strong demand within the EU EU Directive 63, to reduce the use of animals for scientific purposes and instead to use alternative non-animal approaches to fulfil regulatory testing requirements where possible.
Another important aspect of current practice is that carcinogenicity testing is rarely conducted under the REACH legislation unless triggered by specific alerts or exposure conditions i. This represents a potential protection gap, especially for non-genotoxic carcinogens that, when not classified for any other hazard property and not identified as such in limited repeated dose toxicity studies could go unidentified EC Regulation , ; ECHA R7a, ; Jacobs et al.
In the case of cosmetic ingredients, for which in vivo testing is banned EC Regulation , , the assessment of carcinogenicity relies on alternative testing approaches only. In the case of new ingredients that do not fall under other regulations, an in vitro genotoxicity test battery remains the main driver for carcinogenicity assessment.
It is worth noting as well that for other sectors, such as pharmaceuticals, there is the proposal to waive the carcinogenicity rodent assay whenever sufficient supporting information is available Braakhuis et al.
The nature of cancer burden and the associated trends, together with changes in exposure patterns of chemicals in the environment need to be considered in anticipating how carcinogenicity assessment should evolve to offer adequate levels of protection to human health. The contribution of different risk factors, the prevalence of certain cancers over others, the evolution of the disease and the link to other morbidities, the exposure to chemicals in occupational or environmental settings, have all to be taken into account in devising cancer prevention strategies, which include a proper assessment of chemical carcinogenicity.
Consequently, the approaches and test methods in use in regulatory toxicity testing need to be continuously adapted. Initiatives are already underway to utilise new data- and knowledge-driven approaches in carcinogenicity assessment, which profit from the involvement and cooperation of both scientists and regulators from different product sectors. The integration of available information on relevant endpoints, including from epidemiology, traditional and alternative toxicology test systems, together with novel data streams, is undoubtedly considered a way forward to address in the short-term the limitations of the current carcinogenicity testing paradigm Corvi et al.
Here, by broadening the context of regulatory toxicology to include more human specific cancer disease related-issues we emphasise a number of elements that we consider instrumental in providing some options to meet the future needs of carcinogenicity testing. One of the limitations of the current carcinogenicity testing paradigm, based on the 2-year rodent bioassay and chronic toxicity studies, is the difficulty to properly target the potential of a chemical to induce a specific type of cancer Thayer and Foster, This is because the traditional animal studies were designed to identify any possible cancer.
On the other hand, specific assessments on a routine basis for each cancer type are unlikely to be economically and practically feasible, given the huge number of chemicals in need of safety assessment. As described above, recent cancer trends in mortality, incidence and prevalence Bray et al. We therefore recommend prioritising the carcinogenicity assessment of chemicals for their potential to contribute specifically to the development of these four cancers.
For this purpose, a number of options are available to address these specific cancers within toxicity testing strategies. One option is to investigate the role of specific biomarkers that describe signalling pathways driving carcinogenesis in the tissues of interest for the four cancer types.
The identification of signalling pathways that control cell progression, apoptosis or other common hallmarks of cancer are currently used to describe mechanisms and differences between individual tumours or tumour subtypes e. Such information is currently used in cancer research to identify causes of cancer and potential therapeutic targets Sanchez-Vega et al. A number of recently developed in vitro and in vivo cancer models, which provide detailed information on the mechanisms leading to the different cancers, can be used in regulatory toxicology.
We recommend prioritising the development of models that detect specific traits of the most prevalent tumours e. For example, cell culture methods for genetically predisposed breast or colon cancer are already being used in biomedical research Janik et al. Also, 3D models including organoids are currently being investigated for their potential to accurately model physiology, shape and dynamics of colorectal and prostate cancers Phillips, ; Vlachogiannis et al.
Furthermore, biomarker gene signatures currently in use for early cancer diagnosis and clinical treatment decisions can be exploited to prioritise chemicals in need of thorough assessment for a specific cancer type. Grashow and co-workers Grashow et al. The authors have identified several occupational and environmental chemical classes that increase breast cancer risk. However, thousands of chemicals remain untested for their breast carcinogenic potential.
Therefore, the authors have used biomarker gene kits from clinics to prioritise and curate a panel of genes which can serve as a biomarker of mammary toxicity and breast carcinogenesis Grashow et al. The advantage of using biomarker gene signatures lies in their applicability to different test systems: experimental in vivo or in vitro studies and in vitro High-Throughput Screening HTS.
A second option for adapting carcinogenicity assessment to evolving cancer scenarios is to make better use of knowledge of human physiology and pathophysiology deriving from research on human cancer biology, clinical studies and human biomonitoring.
All these provide large amounts of relevant data that can inform toxicity studies. Specific human relevant effects and events involved in the development of cancer disease in humans also represent important information. For example, immune effects, inflammatory events, epigenetic modifications, hormone alterations, including of the non-pituitary axis e. Insulin Growth Factor 1, IGF-1 have been clearly identified as intermediate events in the carcinogenesis process Jacobs et al.
New techniques and novel methods to accurately investigate such events are also becoming available and can be used to enhance standard toxicity studies Smith et al. This means opportunities to design fit-for-purpose studies based on more human-relevant data. In this direction, although not overcoming all the uncertainties of standard in vivo studies, the recent update of standard day and day repeated dose toxicity studies OECD TG , ; OECD TG , and the inclusion of endocrine disruptor assessment into legislation represent another step toward an improved assessment of carcinogenicity.
These initiatives are expected to have a significant impact on the identification of endocrine disruptors and eventually those chemicals with the potential to induce hormone-related cancers ECHA and EFSA Guidance Document, A significant impact is also expected from the on-going OECD project related to the development of an integrated approach to testing and assessment IATA for non-genotoxic carcinogens based on the inclusion of more human-related effects Jacobs et al.
As mentioned above, increased cancer risk has been associated with several chronic disorders such as cardiovascular disease, diabetes, chronic kidney disease, and pulmonary disease Tu et al. These include metabolic disorders that share similar signalling pathways and risk factors with breast, colon and prostate cancer Persano et al. Information on the links with those diseases should also be taken into account to better design testing strategies and be able to discriminate between chronic effects that may or may not lead to cancer.
For example, in addition to environmental carcinogen exposures, a hormone-mediated difference in susceptibility to breast cancer has been observed among US women of different ethnic backgrounds, with the Afro-American ethnic group being more susceptible.
A number of studies have also described interactions in the development of cancer in migrant populations. Asians or South Americans moving to North America or Europe and acquiring westernised life styles have shown increased cancer susceptibility compared to their populations of origin; in this context epigenetic modifications seem to play a key role Martin, Additionally, endocrine disrupting chemicals have been reported to initiate or exacerbate obesity, a cancer-predisposing condition Karoutsou and Polymeris, Research and human epidemiology studies have identified critical windows of susceptibility that can increase cancer risk Moirano et al.
In the case of breast cancer for example, gestation, early childhood, puberty and pregnancy may represent windows of susceptibility to environmental insults Gopalakrishnan et al. However, current animal-based toxicity test guidelines do not allow the study of carcinogenicity within specific windows of susceptibility.
One adaptation in the conduct of in vivo studies is represented by the choice of the appropriate age of the experimental animal. However, the use of this option is limited by the lack of human relevance and other uncertainties Thayer and Foster, ; Gopalakrishnan et al. The use of recently developed in vitro models of human cancer stem cells CSCs , iPSCs which play a key role in tumour formation Persano et al.
Finally, we recommend that information on cancer aetiology and evolution in humans should be also interpreted in light of the impacts of policies currently in place. This information is crucial to better understand the evolution of the disease in the exposed population, to interpret the links with other diseases or cancer-predisposing conditions and potential toxic effects, and to determine the relative contribution of different risk factors Martin, It also helps to identify the most prevalent specific endpoints or mechanisms that should be included in the carcinogenicity assessment.
To address the continuous change of chemicals present in the environment and evolving exposure scenarios, we recommend furthering the identification and use of biomarkers of exposure, effect and susceptibility. Biomarkers give evidence of association between exposure to specific chemicals and a carcinogenic effect and may provide information on mode of action. They provide a range of possible measurements from systemic exposure to resulting causal events in the process of carcinogenesis.
The use of biomarkers has been recommended by the UK Committee on Carcinogenicity to establish recent exposures to actual or potential carcinogens not only in humans but also in experimental animals Committee Carcinogenicity UK, Biomarkers of exposure, referring to chemicals or metabolites measured in human biological media, provide a valuable means of tracking exposure levels in the general population and in subgroups with unusual exposures or vulnerabilities to certain diseases including cancer.
Biomarkers of exposure can approximate internal dose and identify highly exposed groups Rudel et al. Data from biomonitoring and biomarkers of exposure can be used as reference-values in risk assessment or guide the screening of potentially bio-accumulating chemicals Neveu et al. Also, even if the exposure in occupational settings is typically higher than for consumers, it represents a relevant source of information on general chemical exposure effects and health impacts.
In this context, the information gathered through the on-going European Initiative HBM4EU is expected to improve risk assessment by providing better evidence of the actual exposure of the population to chemicals, along with contextual information on possible health effects HBM4EU, In fact, human biomonitoring in Europe has relied on well-established national programs in a number of EU countries Ganzleben et al.
However, such information is accepted and considered to give added value in the exposure assessment both for workers and consumers. Biomarkers of exposure can also be used to monitor chemical combination mixture effects within changing chemical exposure scenarios.
For example, a number of ongoing EU research projects are addressing research gaps in the area of mixture effects, including the development of joint epidemiological-toxicological approaches for mixture risk assessment and for prioritising mixtures of concern Bopp et al.
Other projects are also expected to be valuable for carcinogenicity assessment. In addition, biomarkers of effect which can describe a key event implicated in a carcinogenic mode of action such as genotoxicity, changes in hormone levels, evidence of cell-specific toxicity e.
For this purpose, the Adverse Outcome Pathway framework is an effective means to synthesise the relevant mechanistic knowledge in a form suitable for a regulatory context Langley et al. Finally, furthering the investigation and use of biomarkers of susceptibility, acquired or inherited, which describe an individual's susceptibility to a specific cancer is important to better characterise the exposed population and eventually to identify individuals at high risk.
For example, different genetic polymorphisms e. In addition, genetic susceptibility has been suggested to play a role in one's response to environmental chemical exposures. Cancer Genomics Research. Research on Causes of Cancer. Cancer Prevention Research. Cancer Treatment Research. Cancer Health Disparities. Childhood Cancers Research.
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