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Carcinogens, how do they work?

Carcinogens, how do they work?


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The easiest carcinogenic thing for me to grasp is radiation, as it directly messes with DNA. Then it seems there are other compounds that simply mimic hormones, but these shouldn't necessarily cause cancer, right? Then there are things that can accelerate mitosis or mess with other processes, which can inadvertently mess with DNA. So my question is, in general, how many different flavors of carcinogens are there? I know there are a lot, but can someone list a good few? Maybe some examples? I'm most interested in how plastics and things like smoke cause cancer. I think a few examples would be best in aiding my understanding. Thank you!

Edit: I also just realized this is not the Chemistry This Site, I think I am more interested in the chemistry side of this question, but it might need to be migrated.


"So my question is, in general, how many different flavors of carcinogens are there?" As mentioned in the comments, almost all carcinogens act by damaging DNA. In general there are three ways to do this:

Alkylation, a good example is pyridine. These compounds covalently modify the DNA and either cause a mutation by misincorporation during DNA replication (where the wrong base is incorporated across from the alkylated base), or by generation of double strand breaks during DNA replication that result in a mutations during the repair process (the details of which are not in-scope here).

Intercalation, my favourite example being ethidium bromide. These compounds literally insert themselves between the bases of the double helix, where they cause "fork collapse" during DNA replication, and the ensuing repair process mutates the DNA.

Ionization through radicals. Yes, carcinogens can generate radicals that will generate DNA damage. A good example is doxorubicin, which is a highly effective chemotherapeutic, but also a carcinogen in its own right. Some heavy metals can also generate radicals under the right circumstances. These compounds typically oxidize the bases of DNA, and result in broad misincorporation during DNA replication. Radicals can also result in breakage of the phosphodiester backbone, which cause mutations during repair. This mechanism is taken advantage of in some methods for studying the primary and secondary structure of RNA molecules, and in "foot printing" methods. Incidentally, it is this mechanism of carcinogenesis that causes antioxidants to be associated with the prevention of cancer. Compounds like vitamin C soak up the radicals generated by the carcinogen (or radiation), thereby preventing the damage from occurring.

An interesting point: pyrimidine dimers, which are generated whenever you get a sunburn, are a carcinogenic form of DNA damage somewhere between the ionization and alkylation mechanisms. UV light induces a redox reaction that results in covalent linkage of two neighboring pyrimidines. A dedicated repair process can cause a mutation at the site of the dimer.

However, the take home point is that the DNA damage itself is not usually the mechanism of mutation! Mutation occurs when the damage is repaired, either as part of a dedicated repair process, or by (non)homologous recombination after a stall in DNA replication.

I hope this answers your question. It is a complicated subject, and I doubt I covered everything here.


Carcinogen

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Carcinogen, any of a number of agents that can cause cancer in humans. They can be divided into three major categories: chemical carcinogens (including those from biological sources), physical carcinogens, and oncogenic (cancer-causing) viruses.

Most carcinogens, singly or in combination, produce cancer by interacting with DNA in cells and thereby interfering with normal cellular function. This ultimately results in the formation of a tumour (an abnormal tissue growth) that has the ability to spread (metastasize) from its site of origin and invade and cause dysfunction of other tissues, culminating in organ failure and death. The two primary mechanisms by which carcinogens initiate the formation of such tumours is via alterations in DNA that encourage cell division and that prevent cells from being able to self-destruct when stimulated by normal triggers, such as DNA damage or cellular injury (a process known as apoptosis). There also exist carcinogens that induce cancer through nongenotoxic mechanisms, such as immunosuppression and induction of tissue-specific inflammation.

More than 400 chemical agents have been listed as carcinogenic, probably carcinogenic, or possibly carcinogenic by the International Agency for Research on Cancer (IARC), a branch of the World Health Organization that monitors cancer occurrence worldwide and performs epidemiological and laboratory investigations to understand the causes of cancer. Among the carcinogenic substances listed by IARC are a variety of chemical effluents from industry and environmental pollutants from automobiles, residences, and factories. One such example is acrylamide, which is considered a probable carcinogen in humans and is produced as a result of industrial processes and cooking certain foods at high temperatures. It can be released into the environment through its application in wastewater treatment and its use in grout and soil-stabilizer products. Other examples of chemical carcinogens include nitrosamines and polycyclic aromatic hydrocarbons, which are found in tobacco smoke and are associated with the development of lung cancer.

Physical carcinogens include ultraviolet rays from sunlight and ionizing radiation from X-rays and from radioactive materials in industry and in the general environment. Repeated local injury (e.g., wounding) or recurring irritation (e.g., chronic inflammation) to a part of the body are other examples of potential physical carcinogens.

A number of viruses are suspected of causing cancer in animals, including humans, and are frequently referred to as oncogenic viruses. Examples include human papillomaviruses, the Epstein-Barr virus, and the hepatitis B virus, all of which have genomes made up of DNA. Human T-cell leukemia virus type I (HTLV-I), which is a retrovirus (a type of RNA virus), is linked to tumour formation in humans.

Some—not all—cancers are heritable in the sense that a predisposition exists, awaiting a convergence of carcinogenic influences for cancer to manifest itself. The identification and timely elimination of carcinogens can reduce the incidence of cancer.

This article was most recently revised and updated by Kara Rogers, Senior Editor.


Glioblastoma

Historical overview

The etiology of GBM remains elusive. Several carcinogens found in the environment have been shown to have a causal relationship to cancer. The underlying mechanism is the ability to induce DNA damage that accelerates mutational rates in somatic cells. The clearest risk factor for GBM is radiation. Survivors of the atomic bomb (Life Span Study of Survivors of the Hiroshima and Nagasaki) have had an increased cancer risk during their life span, including brain tumors. 15 Brain cancer risk is dose-dependent even low dose exposure (0.1 Gy) used in medical diagnostics can statistically increase the risk. Patients who have undergone craniospinal radiation for prophylaxis for non-central nervous system (CNS) disease (e.g., pediatric leukemia patients) are at especially high risk for high-grade gliomas in later life. 16,17

Genomic analysis of radiation-induced tumors in the preclinical 18 and clinical setting 19 suggests that ionizing radiation induces a signature pattern of tumor suppressor loss and oncogene activation, which is distinct from de novo tumors with no clear etiology. Risk related to chemical exposure, in particular, Sarin nerve gas in Gulf War Veterans has been documented, 20 although in the vast majority of cases, no etiologic factors can be determined. A possible association between cell phone use and gliomas or acoustic neuromas has been investigated extensively. Current consensus put forth by the International Agency for Research on Cancer (WHO) is that there is no evidence that the electromagnetic fields associated with cell phones are carcinogenic.

Signs and symptoms associated with brain tumors occur as a result of either increased intracranial pressure and/or focal cerebral dysfunction of specific neuronal circuits. The early signs of increased pressure include nausea, vomiting, headache, and change in mental status and are sometimes accompanied by clinical findings of papilledema and loss of retinal venous pulsations. The late symptoms of falcine, uncal, or cerebellar-foramen magnum herniation, associated with clinical findings of hemiplegia, hemianopia, pupillary dilatation, and posturing constitute a surgical emergency for tumor debulking and/or cerebrospinal fluid (CSF) shunting to relieve intracranial pressure and preserve neural tissue. For cerebral hemispheric tumors, the symptoms reflect the neurological functions of the area affected by tumor. For example, temporal lobe tumors in the dominant hemisphere are heralded by the progressive development of contralateral hemiparesis and expressive aphasia, while tumors in the parietal lobe frequently manifest contralateral neglect, sensory inattention, dysesthesia, dyslexia, and dysgraphia. Frequently, temporal lobe tumors that have no overt focal neurological symptoms produce clinically subtle brief focal or partial seizures that may include olfactory or gustatory hallucinations, transient sensations of déjà vu or fear that prior to diagnosis may be misdiagnosed as panic attacks.

A major impact of the development and widespread use of MRI has been the earlier detection of GBM, such that late presentation-associated herniation symptoms have become much less common. Thus earlier detection preserves neurological function and quality of life, making aggressive treatment more feasible although early detection does not alter survival since the major barrier to effective therapy is diffuse infiltration of highly resistant tumor cells. Historically, the treatment for GBM was debulking surgery followed by a 6-week course of external beam radiation. In 2005 the addition of the alkylating agent, TMZ, to radiation therapy increased median survival from 9 to 14.6 months. 21 With the results of two large phase III studies published in 2014, 22,23 no further increase in overall survival has been achieved with any single agent or combination therapy despite extensive basic and clinical efforts (over 1400 GBM clinical trials over past two decades).


Classification of Carcinogens

Carcinogens are classified by The International Agency for Research on Cancer (IARC). The IARC is part of the World Health Organization (WHO) and its main goal is to determine the cancer-causing potential of different substances and classify carcinogens accordingly.

Carcinogens are classified into one of the following groups:

  • Group 1: Carcinogenic to humans
  • Group 2A: Probably carcinogenic to humans.
  • Group 2B: Possibly carcinogenic to humans.
  • Group 3: Unclassifiable as to carcinogenicity in humans
  • Group 4: Probably not carcinogenic to humans

A Rough Guide to the IARC’s Carcinogen Classifications

Click to enlarge

Today’s big news has been the story that the World Health Organisation (WHO) has classified processed meat (including bacon, ham, and salami) as a Group 1 carcinogen. This places it in the same group as smoking, which has led to a number of headlines claiming that it means the risk from the two is the same. It isn’t – and today’s post takes a close look at the International Agency for Research on Cancer’s classification system in order to explain why.

The IARC is a part of the WHO. The IARC’s system was developed to classify different chemical agents, mixtures, or exposures, into one of five groups depending on the evidence for their cancer-causing potential, or carcinogenicity. They began publishing their categorisations in 1971, and since then have assessed over 900 different agents.

The important thing to realise about the IARC classifications is that they don’t assess the level of risk that a particular agent poses with respect to cancer. They simply rank the quality of the evidence of it being cancer-causing. Group 1 is the highest in this regard – the placement of a substance into this classification means that there is sufficient evidence in humans for it causing cancer. Other example group 1 substances include alcohol and smoking.

Red meat, meanwhile, was placed into group 2A. This group is for substances defined as ‘probably carcinogenic to humans’ this means that the evidence in humans is still somewhat limited, but there is sufficient evidence in experimental animals of the substance’s carcinogenic nature. As the evidence decreases, so does the ranking. Group 2B ‘possibly’ causes cancer, group 3 is for substances for which the evidence remains inadequate to state either way, and group 4 is for those for which there is evidence that they are not carcinogenic.

So substances being in the same group tells us the evidence for their carcinogenicity is comparable, but tells us nothing about their relative risks. According to Cancer Research UK, smoking causes 19% of all cancers by contrast only 3% of all cancers are thought to be caused by processed meat and red meat combined. To put this in a little more perspective, it’s estimated that 34,000 cancer deaths worldwide every year are caused by diets high in processed meat, compared to 1 million deaths per year due to smoking, and 600,000 due to alcohol consumption. It’s clear then that the headlines likening the risk of cancer from smoking to that of eating processed meat are well wide of the mark.

It’s also interesting to note the other substances found within the different IARC groups. Group 1, as we’ve mentioned, contains alcohol, which a large number of us drink on a regular basis. It also contains sun exposure – the DNA damage caused by UV radiation from the sun can increase the risk for developing skin cancers.

Red meat falls into the same category, group 2A, as the emissions from frying food at high temperatures. Additionally, exposure to various substances whilst working as a hairdresser or barber is also found in this category. Remember, this simply means the substances or exposures in this group all probably cause cancer, and doesn’t tell us the level of the risks.

When you get down to the other groups, it becomes clear that merely having an IARC classification doesn’t always pose a cause for concern. Substances like coffee are classified as ‘possibly carcinogenic’, simply because the evidence isn’t strong enough one way or the other. In fact, any substance or exposure tested by the IARC gets put into one of these five groups, and there’s actually only one substance that’s been placed into group 4 (probably not carcinogenic) in the history of all the substances that have been assessed.

After all this, you might be wondering what the news on processed meats and red meat actually means for you. Should you give up both and go fully vegetarian? Well, the IARC concluded that eating 50 grams of bacon per day would increase your risk of colorectal cancer by 18%. This sounds pretty significant, but when you look at the actual numbers behind the percentage increase, it makes it a bit clearer. On average, 64 out of 100,000 people develop colorectal cancer per year eating 5o grams of bacon every day would raise your risk to 72 in 100,000.

In short, unless you go on regular bacon binges, today’s news isn’t something to be overly concerned about. Smoking is still a vastly bigger risk factor for cancer than the odd rasher of bacon every now and then. There are health benefits to eating meat, too, so it’s not necessary to cut it out of your diet entirely – simply enjoy it in moderation, as with most things.


UV-induced damage

UV-induced lesions promote chemical modification and structural distortion of DNA by forming photoproducts and oxidative stress. Production of photoproducts, such as cyclobutane pyrimidine dimers (CPDs), pyrimidine-(6𠄴)-pyrimidone photoproducts and their dewar isomers, is achieved through the direct absorption of UVB (290� nm) incident photons by DNA bases and methylation of cysteine bases [47,48]. CPDs account for 75% of the mutations, which are induced by UV [47,49]. T-C and C-C CPD lesions are predominant in the tumour suppressor TP53 and in patients with skin cancer. T-T CPDs are less persistent as eradication of these dimers is induced by insertion of adenine bases by DNA repair mechanisms [17]. Lesions that are difficult to remove result in the following: stalling of DNA and RNA polymerase, reduction in DNA replication, protein synthesis and mRNA synthesis [49].

UVA (320� nm), a poorly absorbed radiation by DNA [50] with an unknown mutagenic effect, is suggested to be associated with promoting DNA damage by oxidative stress through an activation-independent route [17,50�]. UVA photons absorbed by photosensitisers promote photo-oxidation reactions largely giving rise to single oxygen molecules or highly reactive electrons, which subsequently target guanine bases for hydration and deprotonation. Hydration of guanine bases promotes production of 8-oxo7,8-dihydroguanyl (8-oxodGuo) radicals which are considered to be a miscoding lesion (a lesion capable of base pairing with either a cytosine or/and adenine residue) in DNA and a marker for oxidative stress [5,51]. UV-derived 8-oxodGuo radicals have not been shown to promote G:T transversions in mammalian cells which are a common hallmark for 8-oxodGuo-induced mutations [51,52]. However, these lesions are known to cause molecular distortion by changing the structure of purine bases within DNA, but other mutagenic factors are likely to be linked with UVA-induced damage [48].


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I am going to hope that most of the questions in these comments were to point out flaws and omissions in the original article.

Carcinogen is a broad term, comprised of a growing number of substances/chemicals that react in your body and with your cells to cause "free radicals" or cells with a damaged dna/rna component causing it to replicate beyond its normal design, possibly creating mutated cells without any purpose other than to absorb body resources and continue replicating.

I believe the by-product comment about chlorine has to do with the body's natural processes when encountering chlorine, causing the body to create a carcinogen in response. This also occurs within the lungs with tobacco, according to a relatively recent study. The evidence suggesting this occurs with chlorine is still unproven, but considering it is added to drinking water along with fluoride, as well as in pools and certain disinfectants, it definitely comes into contact with human beings on a pretty regular basis.

UV rays are not inherently carcinogenic, but the direct sunlight, when over-exposure occurs (tanning/burning), can damage skin cells, causing them to also become free radicals. Considering UV rays aren't a substance/chemical, I don't know if they are classified as carcinogens or not. You will notice warnings at any tanning bed you frequent, and will soon notice an increase in things like health insurance premiums if tanning is a common hobby. I suspect it's only a matter of time before this becomes a screening question, as its link to melanoma is concrete and well founded.

Cancer being biased towards poor people is a ridiculous statement, as there are so many common carcinogens in both the poor and wealthy worlds that I suspect the rates are somewhat similar. I assume survival rates are a different story. Now that's a really sad thought.

The answer above referring to the time frames of tobacco/cannabis/alcohol were introduced being linked to their legality is spot on. It's also worth mentioning that there are a ridiculous number of studies on the topic of cannabis and cancer risk, with the majority citing no/minimal risk, especially in comparison. Burning anything results in dangerous byproducts, but it would seem that marijuana has essentially no cancer risk when ingested by other means. (Unlike tobacco, where chewing tobacco and smokeless vapors are still cancerous, if somewhat less so).

I will add, that expensive and club based drugs, often linked to a higher status in life, like cocaine, have a much more clearly documented link to diseases and deaths. Drinking alcohol with cocaine use creates a dangerous poison within the body. Cocaine and other stimulants can be directly linked to heart disease, stroke, seizures and death.

That last part was relatively irrelevant given the microcosm of people, wealthy or otherwise, who I suspect imbibe cocaine on a regular basis -- or otherwise. But it was to reinforce the point that cancerous diseases don't discriminate based on age/race/class like people do -- only on biological factors which may or may not be causally linked to income, but certainly do not correlate to the person's status in life. That applies to smoking and the addiction associated with it as well. anon301402 November 3, 2012

It is not known how much of many of these substances will cause cancer that is why they are still being used. It is difficult to understand why one person who smokes gets lung cancer and another person who smokes doesn't get lung cancer.

Certain carcinogens have been removed from use in products because they have been found to cause cancer in much smaller amounts than previously thought. We don't have all the answers to these questions. seekandfind June 26, 2012

You can quit smoking you just have to be stronger than the temptation. I found out the first time quitting is the hardest, so just do it cold turkey. The night before going to bed, throw out your cigarettes, lighter and ash trays. When you wake up in the morning you will already have gone eight hours with out a smoke. From that point, just take it slow, eat and sleep and resist temptation. Soon, you will have 16 hours.

Try to stay away from people who smoke. Remind yourself that you are quitting for your health. Hours will turn into days and days to weeks. You can do it! anon259293 April 5, 2012

I smoke and I can't stop. I'm 15. How can I quit? anon107461 August 30, 2010

My neighbor bar-b-ques late at night and uses lighter fluid to ignite his charcoal. I have been awakened choking as the fumes enter my open windows. Is there a problem with this for me as my home is filled with his deplorable smoke? anon100333 July 29, 2010

Does glue contain carcinogenic? Because I just got into trouble for having heaps on my hand and had to do a 300 word essay on carcinogens. anon88698 June 6, 2010

The legality of cigarettes and for argument's sake, alcohol, is not a case of what they are, but of the timing in which they were introduced into the society and made legal.

If cannabis had been brought forward around the time that tobacco was made legal there could be a whole different outcome.

Conversely, if tobacco were to be introduced today, it probably wouldn't pass and would be illegal. anon60184 January 12, 2010

if uv rays contain carcinogens, then the whole world should suffer from cancer, especially sports men and women, building workers etc.

It's really sad that mostly poor people are the sufferers. While people trey to maintain the environment clean, it's difficult for them to stop smoking. So the world is helpless. anon60169 January 12, 2010

i really want to stop smoking so i am going to do it cold turkey because i heard it works best. anon55832 December 9, 2009

Is the drug Klion a carcinogen? anon52786 November 17, 2009

i smoke i really want to stop but it is really hard. if i was you, trust me -- don't ever smoke. anon44573 September 9, 2009

I am an ovarian cancer patient and I take a juice 30 milliters twice a day which has Sodium Benzoate q.s. Is it harmful for me? Does it have any carcinogens? anon43039 August 25, 2009

how are you able to get cancer if you can't get a hold of a carcinogen?

Carciogonic is in room spray also. It is dangerous to our health. So use it carefully. Don't spray heavily. Spray one or two times slightly. vspaliwalkt July 14, 2009

Most of the mineral water contained in plastic bottle is carcinogenic and very "dangerous" for human health.I raised this matter some 12-15 years back and all these disposable plastic plates,glass and containers are having a layer of Monomers and Plasticizers,which usually takes strong rinsing and washing for removal.

As per knowledge no one is doing that properly. Even the big and established brands are avoiding such measures for removal.

Some countries like Bangkok and Philippines already started using glass bottles instead of plastic bottles for mineral water.

I personally suggest please take drinking water from your home in a well used and thoroughly rinsed plastic bottle. That would be better for your health and also avoid eating in disposable plates if possible. --Vijay Singh Paliwal, Kota,India anon35592 July 6, 2009

You say byproducts of chlorine are capable of causing a range of illnesses including lung cancer. First, a byproduct by definition is something made in the production of something else. So, unless I use the other products made in the process of producing chlorine along with it, it will not cause cancer right? Second, making broad brush statements such as this does compromises the integrity of this web site! beckyboo1995 March 9, 2009

Cigarettes contain more carcinogens than cannabis so why are they legal?

Please write back, this is for my biology homework. Parents evening is coming up and this is *the* piece of work that we are being judged on.

if carcinogen can cause cancer why it was used as a chemical ingredient? anon9633 March 10, 2008

what is the difference between a carcinogen and a cocarcinogene? give examples

it seems like everything these days are carcinogenic!! you also hear a lot about free radicals. are they related to carcinogens, or do carcinogens create free radicals in our bodies?


How Can Identifying and Measuring Exposures to Environmental Carcinogens Help Prevent Cancer?

A recent estimate suggests that more than 40 percent of cancers could be prevented. Modifiable factors linked to cancer include tobacco use, obesity, alcohol consumption, and exposure to ­environmental carcinogens, which are substances in our surroundings that can cause cancer and may facilitate progression of the disease.

Environmental carcinogens could be present in our air, water, or food. While some of these carcinogens have been identified, scientists believe that current measures to mitigate our exposures are inadequate. Other carcinogens present in our environment have yet to be fully defined.

To address these issues, the AACR is hosting a conference focusing on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention next week in Charlotte, North Carolina. This meeting will review current advances in the field with the goal of sparking ideas and discussion about novel ways to prevent cancer.

We had the opportunity to speak with the conference cochairs – AACR Past President Margaret Kripke, PhD, FAACR and Ernest Hawk, MD, MPH, both from The University of Texas MD Anderson Cancer Center, and Timothy Rebbeck, PhD, from the Dana Farber Cancer Institute and the Harvard T.H. Chan School of Public Health – about what to expect at the upcoming meeting.

What prompted this conference about environmental carcinogenesis, and what is the broad scope of this meeting?

Kripke: Several years ago, I was a member of the President’s Cancer Panel, and we published a report highlighting ways to reduce cancers caused by environmental factors. For me, this was a profoundly eye-opening experience. It turned out that many of the assumptions that I had – such as rigorous testing and regulation of potentially carcinogenic substances prior to their public availability – were largely untrue. Since that time, I’ve been interested in trying to raise the visibility of this issue, because reduction of exposure to these carcinogens in the environment is a potential way to prevent many cancers.

Hawk: There’s been a lot of focus over the last two decades on individual behaviors – such as diet and lifestyle – as modifiable risk factors for cancer prevention. However, we know that the environment plays a very big role in interacting with our genome and can have an effect on cancer incidence and progression as well. During this meeting, we’ll talk about known toxins in the environment, how these toxins interact with the genome, the best way to measure exposure to such toxins, and methods to prevent and facilitate the early detection of cancers caused by environmental carcinogenesis. This will help us to identify some of the remaining questions in the field so that we can better learn how to intervene in the future.

Rebbeck: There’s a lot of misinformation – both in the public and in the scientific community – about true environmental carcinogens the data are often inconsistent, and the messages delivered are not always accurate. This conference is very important, because it will help us to further delineate the carcinogens that are present in our environment and foster discussion about ways to mitigate our exposure to carcinogenic compounds.

Can you tell us about some of the highly rated abstracts that will be discussed at the meeting?

Kripke: There’s an entire plenary session devoted to this area which will highlight important topics in the field. The first talk focuses on nitrates in United States drinking water and how that contributes to the overall cancer burden. This is a major issue, and should be of great interest to the public, because the ingestion of nitrates is associated with increased risk for multiple types of cancer.

A second talk will discuss how fine particulate matter – or air pollution – can affect mortality among young individuals with cancer. While the incidence of some cancers, such as those related to tobacco use, has declined in recent decades, the incidence of childhood cancers has increased in the same timeframe. In addition to this talk, I believe that several poster presentations will focus on environmental agents that could be fueling this troublesome trend.

Can you talk about the plenary sessions focused on pathways to prevention and early detection?

Hawk: One of the key topics that will be discussed is the idea of “precision prevention,” the notion that we can combine an individual’s genome with an envisioned biomarker to measure their lifetime exposures to carcinogens, or better yet, measure the cumulative impact of those carcinogenic exposures on the genome to tailor preventive cancer measures. The final talk in this session, for example, will focus on characteristic landmark aberrations from UV exposure that can be detected in the genome. These “sentinels” could help us to determine how much UV damage an individual has accrued over their lifetime, which can be used to predict skin cancer risk.

Another interesting topic centers around the microbiome. One of the presentations will focus on recent advances in microbiome research and how the microbiome may influence responses to carcinogenic exposures.

Rebbeck: Public engagement is key to addressing prevention – there are a few issues that need attention. First, the public is often not adequately informed about how environmental exposures can affect cancer risk we need better evidence-based education to convey to the lay public about what substances are actually toxic. Second, scientists need to find ways to better interact with communities that are affected by the issues under study. Often, scientists identify a problem and study it, but they may not understand the context of the issue if they’re not living in that community. We can do a better job if we understand the circumstances that surround the issue and determine how the problem can be addressed so that it has the most translational impact down the road.

Another important issue is that of cancer disparities, which can exist because some individuals are more likely to be exposed to carcinogens based on where they live or work. Cancer disparities are unacceptable in our society we need to find ways to help those who are at increased risk due to these specific exposures. Furthermore, we need to apply the knowledge gained from the studies on disparities to help eliminate exposure-related cancers in the entire population.

What are some of the challenges and next steps in this field?

Kripke: I think that the real challenge in the field is this – how do we translate all of this knowledge that we’ve accumulated about known environmental carcinogens into something that’s useful for reducing the burden of cancer? To address this issue, we need to move outside the realm of cancer medicine and dive into the realm of public and economic policy. We need to identify what laws need to be changed or addressed in order to remove some of these harmful substances from the environment to ultimately prevent the burden of many cancers.

Hawk: One possible reason that cancer is largely an age-related disease is because cumulative exposure to carcinogens across our lifetimes can affect our cancer risk. I think that one of the biggest challenges in the field centers around identifying one or more biomarkers that reflect such exposures, or the cumulative damage they’ve wrought, over time in healthy individuals. These biomarkers could help us to determine which asymptomatic individuals have a higher risk of developing cancer(s), and my ears will be particularly attuned to progress in this area.

Rebbeck: A central challenge in the field is identifying the most accurate ways to measure environmental exposures, and translating that information into risk stratification. Another main challenge is intervention – once we’ve been exposed to these carcinogens, is there a way that we can intercede and prevent the development of cancer? I anticipate that these challenges, among others, will be major topics of discussion at the meeting.

Interested in learning more about this meeting? Hawk shared his thoughts about the conference in this video interview:


Introduction

DNA damage occurs through exogenous and endogenous processes. Carcinogens, irrespective of their origin, have the ability to evoke the development of DNA damage through a variety of mechanisms. This includes, for instance, covalent binding of carcinogen with DNA or DNA double-strand breaks (DSBs) formed as a result of ionising radiation (IR)-induced free radical generation [1,2]. Carcinogens are categorised as being chemical or physical agents [3], causing DNA damage attributable to their physico-chemical properties, such as DNA molecule distortion or DNA cross-linking [3–6]. Table 1 shows a small subset of environmental and/or dietary carcinogens however, there are multiple other examples to which humans are potentially exposed (Table 1).

Candidate agents . Overview . References .
Heterocyclic aromatic amines (HAAs) HAAs are activation-dependent, heat-induced mutagenic agents predominantly present in foodstuffs containing nitrogenous and creatine components. Molecular structure of HAAs is dependent on the temperature and level of heat transferred to the food. Can generate SSBs, chromosomal aberrations and DNA adducts in guanine-rich regions. Activated metabolites can attack N 2 -position of guanine (most common) or C8-atom of guanine (occurs less frequently). [13–15]
Polycyclic aromatic hydrocarbons (PAHs) Combustion of organic matter results in the generation of PAHs. These are the most abundant indirect-acting carcinogens to which humans are exposed to on a daily basis. Exposure has been associated with the development of breast, skin or lung cancer. Bioactivation of PAHs is required in order for these agents to exhibit mutagenic properties, which is primarily mediated by cytochrome P450 enzymes. Bioactivated metabolites target multiple genomic sites, including guanine and adenine bases via PAH diol epoxides. This results in the generation of bulky BPdG chemical DNA adducts examples include quinone-mediated cross-linking of N7 position of guanine and N3 of adenine. [11,16]
Ultraviolet (UV) Direct- and indirect-acting genotoxic cancer-causing agent, primarily absorbed by epidermal components, such as DNA bases (thymine and cytosine) and proteins. This agent is implicated in the causation of skin tumours by targeting pyrimidine bases. Exposure to the epidermis and dermis induces both the up-regulation of cell proliferation and photoproduct generation, including CPDs and (6–4) pyrimidine pyrimidines. [5,17–19]
Aristolochic acid (AA) Naturally derived acids from Aristolochiaceae plants. Ingestion of these carcinogens shown to be largely associated with nephrotoxicity of the renal cortex and further damage to the bladder and liver very likely due to the development of bulky chemical DNA adducts. Most abundant and mutagenic form of DNA adduct associated with AA is dA-AA. In exons 2–11 of TP53, bulky chemical DNA adducts result in mutations, primarily of A:T base pairs. [20–24]
Nitrosamines Metabolism of nitrosamines subsequently induces alkylating DNA damage via the formation of DNA adducts such as O 6 -alkylguanine, oxidative stress and production of diazonium ions. Humans are exposed to these agents through various foods and tobacco smoke. [25,26]
Mycotoxins Mycotoxins are fungal-derived metabolites, which primarily contaminate food. The most commonly found mycotoxin is aflatoxin B1, discovered in the early 1960s. These are indirect carcinogens, which require bioactivation via CYP to generate DNA adducts. Adduct formation targeting guanine bases, which induces G → T transversions at codon 249 in TP53. [27–29]
Ionising radiation (IR) Exposure to ionising radiation induces DNA damage in an indirect or direct manner. The indirect carcinogenic effect is mediated via water radiolysis, which promotes the production of ROS resulting in oxidative damage, which can result in SSBs. The direct effect involves direct interaction of electrons with DNA resulting in molecular distortion and DSBs. [5,6]
Asbestos Asbestos is highly carcinogenic and used historically in industry and household applications. Exposure to fibres is directly linked to asbestosis, pleural plaques and mesothelioma. Dimension, shape and chemical composition are factors in asbestos pathogenicity. Damage occurs through oxidative stress (may give rise to DNA strand breaks), fibrosis and interaction with the mitotic apparatus of dividing cells. Synergism in the causation of lung cancer is seen with other mutagens, including PAHs, due to asbestos' insoluble core via which adsorbed carcinogens are delivered to target sites where they exert their genotoxic effects. [30,31]
Nanoparticles (NPs) Nanotechnology engineering has seen increasing usage of nanoparticles in medical, cosmetics and electronic industries. NPs have one dimension <100 nm, aiding cell penetration following inhalation, dermal or oral exposure with consequent ability to cause DNA damage. Damage can be direct and genotoxic effects include DNA adducts resulting from oxidative damage, epigenetic changes and DNA strand breaks. [32–34]
Candidate agents . Overview . References .
Heterocyclic aromatic amines (HAAs) HAAs are activation-dependent, heat-induced mutagenic agents predominantly present in foodstuffs containing nitrogenous and creatine components. Molecular structure of HAAs is dependent on the temperature and level of heat transferred to the food. Can generate SSBs, chromosomal aberrations and DNA adducts in guanine-rich regions. Activated metabolites can attack N 2 -position of guanine (most common) or C8-atom of guanine (occurs less frequently). [13–15]
Polycyclic aromatic hydrocarbons (PAHs) Combustion of organic matter results in the generation of PAHs. These are the most abundant indirect-acting carcinogens to which humans are exposed to on a daily basis. Exposure has been associated with the development of breast, skin or lung cancer. Bioactivation of PAHs is required in order for these agents to exhibit mutagenic properties, which is primarily mediated by cytochrome P450 enzymes. Bioactivated metabolites target multiple genomic sites, including guanine and adenine bases via PAH diol epoxides. This results in the generation of bulky BPdG chemical DNA adducts examples include quinone-mediated cross-linking of N7 position of guanine and N3 of adenine. [11,16]
Ultraviolet (UV) Direct- and indirect-acting genotoxic cancer-causing agent, primarily absorbed by epidermal components, such as DNA bases (thymine and cytosine) and proteins. This agent is implicated in the causation of skin tumours by targeting pyrimidine bases. Exposure to the epidermis and dermis induces both the up-regulation of cell proliferation and photoproduct generation, including CPDs and (6–4) pyrimidine pyrimidines. [5,17–19]
Aristolochic acid (AA) Naturally derived acids from Aristolochiaceae plants. Ingestion of these carcinogens shown to be largely associated with nephrotoxicity of the renal cortex and further damage to the bladder and liver very likely due to the development of bulky chemical DNA adducts. Most abundant and mutagenic form of DNA adduct associated with AA is dA-AA. In exons 2–11 of TP53, bulky chemical DNA adducts result in mutations, primarily of A:T base pairs. [20–24]
Nitrosamines Metabolism of nitrosamines subsequently induces alkylating DNA damage via the formation of DNA adducts such as O 6 -alkylguanine, oxidative stress and production of diazonium ions. Humans are exposed to these agents through various foods and tobacco smoke. [25,26]
Mycotoxins Mycotoxins are fungal-derived metabolites, which primarily contaminate food. The most commonly found mycotoxin is aflatoxin B1, discovered in the early 1960s. These are indirect carcinogens, which require bioactivation via CYP to generate DNA adducts. Adduct formation targeting guanine bases, which induces G → T transversions at codon 249 in TP53. [27–29]
Ionising radiation (IR) Exposure to ionising radiation induces DNA damage in an indirect or direct manner. The indirect carcinogenic effect is mediated via water radiolysis, which promotes the production of ROS resulting in oxidative damage, which can result in SSBs. The direct effect involves direct interaction of electrons with DNA resulting in molecular distortion and DSBs. [5,6]
Asbestos Asbestos is highly carcinogenic and used historically in industry and household applications. Exposure to fibres is directly linked to asbestosis, pleural plaques and mesothelioma. Dimension, shape and chemical composition are factors in asbestos pathogenicity. Damage occurs through oxidative stress (may give rise to DNA strand breaks), fibrosis and interaction with the mitotic apparatus of dividing cells. Synergism in the causation of lung cancer is seen with other mutagens, including PAHs, due to asbestos' insoluble core via which adsorbed carcinogens are delivered to target sites where they exert their genotoxic effects. [30,31]
Nanoparticles (NPs) Nanotechnology engineering has seen increasing usage of nanoparticles in medical, cosmetics and electronic industries. NPs have one dimension <100 nm, aiding cell penetration following inhalation, dermal or oral exposure with consequent ability to cause DNA damage. Damage can be direct and genotoxic effects include DNA adducts resulting from oxidative damage, epigenetic changes and DNA strand breaks. [32–34]

Exposure to carcinogens can either directly [7] or indirectly [1,8] induce DNA damage. Subsequent repair mechanisms may result in alterations in DNA sequences, i.e. mutations [2,9]. Induced mutations may be initiating events in cancer causation, when the damage is fixed within oncogenes or tumour suppressor genes [10]. Such risk may also be directly influenced by individual susceptibility and genetic instability [11]. For example, in the inherited genetic disorder Xeroderma Pigmentosum (XP), mutations in the XP proteins disrupt DNA repair resulting in the build-up of sunlight-induced lesions in skin DNA and a high rate of skin cancer [12].


New technology tracks carcinogens as they move through the body

Researchers for the first time have developed a method to track through the human body the movement of polycyclic aromatic hydrocarbons, or PAHs, as extraordinarily tiny amounts of these potential carcinogens are biologically processed and eliminated.

PAHs, which are the product of the incomplete combustion of carbon, have been a part of everyday human life since cave dwellers first roasted meat on an open fire. More sophisticated forms of exposure now range from smoked cheese to automobile air pollution, cigarettes, a ham sandwich and public drinking water. PAHs are part of the food we eat, the air we breathe and the water we drink.

However, these same compounds have gained increasing interest and scientific study in recent years due to their role as carcinogens. PAHs or PAH mixtures have been named as three of the top 10 chemicals of concern by the Agency for Toxic Substances Disease Registry.

With this new technology, scientists have an opportunity to study, in a way never before possible, potential cancer-causing compounds as they move through the human body. The findings were just published by researchers from Oregon State University and other institutions in Chemical Research in Toxicology, in work supported by the National Institute of Environmental Health Sciences (NIEHS)

The pioneering work has been the focus of Ph.D. research by Erin Madeen at Oregon State, whose studies were supported in part by an award from the Superfund Research Program at NIEHS for her work at Lawrence Livermore National Laboratory.

"We've proven that this technology will work, and it's going to change the way we're able to study carcinogenic PAHs," said David Williams, director of the Superfund Research Program at OSU, a professor in the College of Agricultural Sciences and principal investigator with the Linus Pauling Institute.

"Almost everything we know so far about PAH toxicity is based on giving animals high doses of the compounds and then seeing what happens," Williams said. "No one before this has ever been able to study these probable carcinogens at normal dietary levels and then see how they move through the body and are changed by various biological processes."

The technology allowing this to happen is a new application of accelerator mass spectrometry, which as a biological tracking tool is extraordinarily more sensitive than something like radioactivity measuring. Scientists can measure PAH levels in blood down to infinitesimal ratios -- comparable to a single drop of water in 4,000 Olympic swimming pools, or to a one-inch increment on a 3-billion mile measuring tape.

As a result, microdoses of a compound, even less than one might find in a normal diet or environmental exposure, can be traced as they are processed by humans. The implications are profound.

"Knowing how people metabolize PAHs may verify a number of animal and cell studies, as well as provide a better understanding of how PAHs work, identifying their mechanism or mechanisms of action," said Bill Suk, director of the NIEHS Superfund Research Program.

One PAH compound studied in this research, dibenzo (def,p)-chrysene, is fairly potent and defined as a probable human carcinogen. It was administered to volunteers in the study in a capsule equivalent to the level of PAH found in a 5-ounce serving of smoked meat, which provided about 28 percent of the average daily dietary PAH intake. There was a fairly rapid takeup of the compound, reaching a peak metabolic level within about two hours, and then rapid elimination. The researchers were able to study not only the parent compound but also individual metabolites as it was changed.

"Part of what's so interesting is that we're able to administer possible carcinogens to people in scientific research and then study the results," Williams said. "By conventional scientific ethics, that simply would not be allowed. But from a different perspective, we're not giving these people toxins, we're giving them dinner. That's how much PAHs are a part of our everyday lives, and for once we're able to study these compounds at normal levels of human exposure."

What a scientist might see as a carcinogen, in other words, is what most of us would see as a nice grilled steak. There are many unexpected forms of PAH exposure. The compounds are found in polluted air, cigarettes, and smoked food, of course, but also in cereal grains, potatoes and at surprisingly high levels in leafy green vegetables.

"It's clear from our research that PAHs can be toxic, but it's also clear that there's more to the equation than just the source of the PAH," Williams said. "We get most of the more toxic PAHs from our food, rather than inhalation. And some fairly high doses can come from foods like leafy vegetables that we know to be healthy. That's why we need a better understanding of what's going on in the human body as these compounds are processed."

The Williams-led OSU laboratory is recruiting volunteers for a follow-up study that will also employ smoked salmon as a source of a PAH mixture and relate results to an individual's genetic makeup.

Some of the early findings from the study actually back up previous research fairly well, Williams said, which was done with high-dose studies in laboratory animals. It's possible, he said, that exposure to dietary PAHs over a lifetime may turn out to be less of a health risk that previously believed at normal levels of exposure, but more work will need to be done with this technology before such conclusions could be reached.

Collaborators on the study were from the Pacific Northwest National Laboratory, Lawrence Livermore National Laboratory, and the OSU Environmental Health Sciences Center.

"Further development and application of this technology could have a major impact in the arena of human environmental health," the researchers wrote in their conclusion.