The Earliest Theories for Cancer
The Science and Medicine of Cancer. There are several ways to interpret the history of cancer recognition and diagnosis and the understanding of cancer biology and pathology as there are commonly understood. The term cancer has a long history of use in medicine, its earliest forms perhaps derived from ancient medical writings that made mention of the various growth or tumors on the body including the traditional and fairly old-fashioned canker or chancre. Without adequate knowledge of the cause for illnesses like canker, even professionals in medicine at time differed greatly in their opinions as to what cancer actually was and whether or not it was often fatal.
This lack of understanding of cancer/canker continued throughout much of the eighteenth and nineteenth century, although at times some scientists were very correct in trying to clarify the notion often taken by even physicians that some illnesses may appear like cancer, but are significantly different that cancer in their effects on the patient and their minimal impact on longevity when compared with similar disease types. For much of the nineteenth century, this lack of understanding even led to the development of numerous remedies or “cures” for cancer, many still popular today, that were indeed quite effective at eliminating some of the ill-states often associated with cancer (to the novice) or canker (to the well-trained physician) or even warts and other uncontrollable skin growths. They rarely, if ever, cured cancer. Even during the early 1900s, the understanding of cancer was still quite limited, as evidence by the reward of the Nobel prize given to a scientists for his explanation that stomach cancer was due to a microorganism residing in the gut (this claim was soonafter rescinded).
Several important actions or discoveries gave way to doctors developing an understanding of what cancer was and how it differed from other diseases. First, a visual inspection of cancer and its growth potential as a tumor had to be more commonplace in the medical school program. Even during the mid-1800s, the use of cadavers in the lab of a medical school still had its limits. Not all doctors had the opportunity to actually see a cancer case as we would truly diagnose such a case today. As a result, unless they were well-trained, even the common regular physicians (MDs) of the mid-nineteenth century might never know if and when they managed to treat cancer for the first time.
Adding to this problem with diagnosis was the popularization of other medical philosophies and practices. The less-informed, less-educated versions of medicine (many even home-trained form of the profession) led to the development of practices in which the doctors adhered to in part what was already taught as commonplace opinions and teachings about cancer/canker, and in part to the professional teachings of what cancer was as indicated by their medical books. It is not unusual during this time to find books that detail the differences between cancer and canker as the latter being less invasive and fatal to the overall person’s well-being and ability to survive the illness. Whereas the regular school-trained physician was finally beginning to understand the “crab” (Latin: Cancer) Hippocrates had written about regarding the behavior of this malady, the oncos or “swelling” described by Roman surgeon Galen seemed to prevail pretty much in the commonplace.
In spite of these significant differences in interpreting cancer, with one set of professional perhaps following the right route to discovery and the other retaining many of the old thoughts and practices, when it came to defining the causes for these two maladies, those untrained in cancer were just as correct in how to deal with it as the highly trained medical professionals. Neither of these professions were effective healers of this disease and neither had a definitive way to tell one type of from the other. For the most part, the cancer therapy for the time was pretty much symptomatic and palliative. Aside from using a watch and wait approach to everything in many cases, it was not unusual to see practitioners latch onto a particular theory, cause and therapeutic practice, often centered on the medicines.
It wasn’t until nearly a century after the formation of various alternative theories and philosophies for treating cancer that cancer became better understood. These improvements in understanding were the result of the evolution of the histology and pathology professions, to such an extent that histologically and even macroscopically, a trained physician could immediately tell the difference between an abnormal skin growth of canker origin versus potential cancer origin. More importantly, the importance of DNA was for the first time better understood and its roles in cell growth and longevity and even carcinogenesis. With the development of the first effective tumor drugs capable of killing documented cancer cases, like the development of mustard poisons during World War II and methotrexate in 1956, that the nature of the tumor and how to treat it were better understood. Ironically, also during this time, a popular liver medicine known for its ability to produce bile flow (taking a pill resulted in yellow stools, signifying the release of bile and cleaning of the liver) was found to be an actual cancer drug that worked at the cell division and nucleic acid (genetic) level, a discovery only made possible due to improvements in our understanding of DNA finalized by around 1962 (Watson-Crick). By the late 1960s and early 1970s, physicians, pathologists and pharmacologists had a fairly accurate and complete understanding of what cancer is and its possible causes. By 1979, a review of the theories for published included for the first time heavy emphasis on the role of chemical in carcinogenesis (Kardinal, 1979).
The Epidemiology of Cancer. The understanding of the cause for cancer took a road parallel to the roads to its theory and treatment. This road is parallel because the proofs for the causes being popularized were more borne by public health and epidemiological thinkers than actual pathologists and physicians. One of the earliest cancer epidemiologists to initiate his research along the right track was Dr. John Hill of England. In 1761 he linked tobacco use in the form of heavy snuff to the various forms of oral cancers he was witnessing. In 1775, a similar association between tumors or cancer and environmental exposure came when Sir Percival Pott (1713-1788) linked scrotal cancer to chimney sweeping profession, due to the exposure of this part of the skin to coal dust and ashes in the chimney as a part of their work.
These two observations of environment linked to cancer or tumor development failed to gain much recognition though for the next one-hundred and fifty years. In 1915, a Japanese physician Katsusaburo Yamagiwa performed a study on rabbits which demonstrated that tobacco relate tar products were capable of producing tumors to develop that were fatal. This ultimately led to the theory that cancer was caused by certain forms of chemical exposure, in particular those related to tobacco and smoking habits.
Over the next few decades, other chemicals were linked to cancer as well. The arsenic contained in pesticides and herbicides was linked to lung and skin cancers. The formaldehyde used by wood product and paper industries was linked to nasopharyngeal (nose-throat) cancer. Mineral oils found in the metalworks industry were linked to skin cancer. The pigments found in hair dyes were found to cause bladder cancer in the hairdressing industry. The highly aromatic hydrocarbons typical of petroleum products and diesel engine exhaust were found to be carcinogenic for bus drivers and train operators. The benzenes found in paints, dye products and various chemical products industries were found to be linked to certain forms of leukemia. The link between chemicals and cancer was pretty much finalized during the 1960s, leading to improved therapies for cancer treatment a decade later.
In the 1979 and 1980s, the benzene theory for cancer was promoted due to certain links documented between certain occupation types and increase cancer incidence. The most common chemical in many workplaces is benzene, and through the efforts of one person’s attempt to draw the links between benzene and cancer during this time, this belief and adherence to the benzene theory have pretty much prevailed. It seems likely that benzene theory defines one small part of the carcinogenic pathway taken to the development of chemically induced tumors that are truly carcinogenic.
There are a numbers of pros and cons to this theory worth mentioning. Its major support relates to the fact that a number of theories have been established suggesting how and why benzene can cause a cancer to develop. In addition, a lot of these studies have even been able to produce supporting documentation for the benzene-cancer link, although this link is often made by different researchers between different forms of cancer, ranging from skin and lung, to liver and blood. In addition, whereas benzene has been linked to certain forms of cancer in specific groups of studies, the same cancer types has an equal number of publications in the medical journals detailing other potential causes for these same forms of cancer.
The major problem with the “benzene theory” for carcinogenesis relates to its wording and the interpretation of this wording both professionally and unprofessionally. There are two major groups of chemicals mentioned in the benzene theory regarding how benzene could cause cancer. The first group of chemicals are in fact benzenes, the second are not, although they are made up of sections that very much resemble benzene. The first group is fairly small in size and capable of undergoing many of the effects as a physical structure described by the researchers supporting this point of view. The much larger benzene-like compounds may have similar features, such as aromaticity and such (described later), but are too large to undergo the same biologic-enzyme-metabolism-related activities the smaller benzene compounds could engage in. This inability of a well documented highly carcinogenic set of chemicals to not behave like benzene at the molecular level in a biological systems suggests there are at least two mechanisms at play in the carcinogenetic pathways each type of chemical follows.
For these reasons, the use of the term “benzene theory” is retained as well as its method for defining at least part of the cancer-inducing steps associated with these chemicals, but other methods of interpreting molecular physics have been employed to apply this theory to other potentially carcinogenic chemicals as well. At times, the ability of a chemical to become carcinogenic, also related to how we have learned that we can chemically treat cancer. So at times these two sets of theories are reviewed alongside each other.
The Benzene Theory for Carcinogenesis
The benzene theory for carcinogenesis states the exposure to benzene or any benzene-derived chemicals can lead to cancer. There are several mechanisms by which aromatic compounds can cause cancer, the evidence for which is somewhat disputable when we take into account the different mechanisms by which benzene has been said to cause the changes in genetic materials typically associated with the initiation of cancer cells.
The toxicologic mechanisms by which benzene results in cancer are of several types, and most likely similar events related to benzene interactions with intracellular chemicals and materials may also take place or involve some sort of involvement of other chemicals that lack the benzene like appearance of many theoretical carcinogens. The following represents three ways in which benzene is displayed in chemical structure drawings, with two polycyclic benzenes in the bottom row. The most important thing to note about these structures are the chemical bond feature referred to as “aromatic” bonds.
Aromaticity refers to a situation when a C=C chemical bond (which is typically considered equivalent to a pair of negatively charged electrons) is allowed to share its electrons with the adjacent carbon bearing a single bond. In essence, the electron pair is shared between two neighbors and the actual charge they possess gets distributed more evenly across all adjacent, involved carbons, so long as there is just one single bond separating the various adjacent atoms. This means that for a molecule to be aromatic bonds, there must be double bonds alternating with single bonds, in an exactly 1:1 nature. Two single bonds in a row does not result in aromaticity between the two double bonds. The unusual occasion when two double bonds are end to end (i.e. -C=C=C- ) also does not represent aromaticity.
To demonstrate how loosely applied this theory is as to aromaticity and its relationship to carcinogenesis, it is helpful to not how similar physical chemical concepts relate to other suspected carcinogens. the simplest chemicals related to carcinogenesis are a breakdwon of benzene that retains its aromaticity and two slightly modified benzene derivatives.
Simple chemical paths linked to benzene-related activities and the development of other suspected carcinogens
This first theory for benzene-derived carcinogenicity is very different in its mechanisms than carcinogenesis induced by molecules that appear to be multiple benzene molecules attached side by side, sharing 2 with each shared chemical bond-defined border, and sharing more that 2 carbons when these borders are shared with more than one other benzene ring structure.
Polycyclic Aromatics
At the molecular level, these two mechanisms at first to be fairly similar, but in terms of size relationships, the two events that take place in order for each chemical type (small versus large) to cause cancer to develop must be very different. The main reason for these differences is molecular size in relationship to the chemicals and surfaces being impacted in order to result in the defective gene, modified protein, or altered biochemical state needed to cause irregular cell growth to commence and a cancer tumor to form.
The simplest explanations given for these two distinctly different cancer-causing mechanisms is that the smaller benzene derivative are capable fo working directly upon other small chemical structure, like the building blocks of certain proteins of DNA and RNA, whereas the larger molecules although capable of interacting with certain surface chemicals, are sometime too big to make it into the nooks or crannies that need to be access in these sensitive protein and nucleic acid structure. The mechanism of ascribed to these chemicals is that they either work in other places, but via similar reactions, to cause changes in other normally stable chemical structure, or that they act as a form of blockade, preventing other chemicals like enzyme and proteins from performing the functions they need to perform to allow for normal cell growth to take place. This latter mechanism of causing cancer is referred to as intercalation, and is much like placing a large physicial barrier in the right place so as to prevent passage along normally travelled routes or pathways related to various forms of chemical synthesis (chromosomal-related, RNA related or simple protein synthesis pathways). When the chemical holds its place in the biosynthetic structure, behaving somewhat like a permanent barrier, it is an intercalator. (This same mechanism by the way is used for the production of cancer drugs as well, mostly because variations on this process can cause the rapidly dividing cancer cells to cease functioning biologically and die.)
Benzenes and Aromaticity at the Next Level
The problem with this theory, once again, is that it doesn’t take into account the structure related reasoning for why other organic compounds like pesticides and herbicides are often considered carcinogenic. We could come up with another theory for this behavior, or try to apply once again the general statements made by the benzene theory to help explain why these agricultural toxins and at time common place household poisons are also capable fo causing cancer to develop.
Halogenic Aromatic Compounds
Another class of chemicals related to carcinogenicity are the halogens. These include Fluorine, Chlorine, and sometime Iodine for the most part. Unlike the more common elements of organic molecules such a Carbon, Hydrogen, Oxygen and Nitrogen, the halogens possess additional electron pairs in their outer orbitals (outer surface of the atom, in theory) that are capable of responding to other local electron pair charges, creating a larger area for the resonance to occur. Although there is no distinct behavior documentable for the behaviors of these pairs with the traditional aromatic pairs, there is considerable evidence demonstrating that the halogens can create havoc with the chemistry and stability of various biochemical paths and their products (genetic and protein materials). It is possible that halogens work differently than aromatically bonded molecules, with both creating effects as the amount of aromaticity or halogenicity increases on a per molecular weight/molecular volume basis.
Reactivity and carcinogenicity based on electron pair availability and source
When reviewing a molecular formula, the following common electron pair sources possibly associated with carcinogenicity are worth noting (in descending order of importance): aromatic rings and halogens (the most important), unstable oxygen sources like peroxides ( – O – O -), and in certain cases Nitrogen (see figure). This information can be used to assess the toxicity and carcinogenicity of groups that might otherwise be considered equal in terms of risk. As an example, one chemical reclass method applied in this was identifying each of the polycyclic aromatics by defining (coding) their core ring followed by numbers indicating numbers of electron pairs in ring, followed by halogens, and numbers of Nitrogens, for example 4R18C9D0H for the polycyclic aromatic, associated with many of the older power facilities (coal is the source), and 0R2C0D4H for the halogenic non-aromatic compound, a common chemical tested for at dry cleaning sites. When working within the same group, like analyzing the toxicity/carcinogenicity of polycyclic aromatics, these bonds demonstrate a fair amount of relationship between chemical make-up, bond formations and carcinogenicity. Likewise, this formula works pretty well with non-aromatic halogenic compounds. Other features often take center stage when comparisons between chemical groups are made, for example to carcinogenicity of the chemical element mercury versus organic mercury sources, or another chemical element like arsenic. All of these also have their own carcinogenic histories, with causes not as easily manageable in the mathematic sense when trying to assign risk to a site based on its chemical make-up and history.
Two commonly cited carcinogens suspected at sites
With diquat, there is a small amount of aromaticity worth noting involving each of the two rings separately. With the paraquat, the aromaticity of one ring is resonant with the same aromaticity noted in the second ring, so this chemical at least conforms more with the benzene theory proposed for carcinogenicity. The added “kicker” to these aromatic molecules is the pseudo-aromatic nature of Nitrogen (N). In this case, the Nitrogen atom is polarized (positive charge – N+), making it more soluble in water, reactive in ecological settings, and more likely to be effective as a poison. This N+ also bears an addition pair of electrons normally not demonstrated in usually chemical structure drawings. This added electron pair can also resonate with ring-pairs if placed in the right position. This not only adds to size of the reactive, resonating, aromatic portion of the molecule, it also changes the molecule by increasing its reactivity. When neutralized by the addition or a negatively charged chemical to this N+, this causes changes in solubility to take place making it more oil or fat-soluble, and capable of entering the human body for example via skin tissue and other biological surfaces.
The chemistry of a purportedly highly toxic class of carcinogens
One of the most commonly discussed group of exposure chemicals are the dioxins. This group of compound has two aromatic rings joined by two oxygen bridges, and with halogens bound to the various available benzene ring attachments available for side group interaction. In terms of chemical form and constituents, this a fairly small molecule in terms of the total negative charges it theoretically bears (44). Because it is a fairly small potential carcinogen, we expect to see a considerable amount of reactivity with biological surfaces and chemicals as the means for it to act as a carcinogen.
There are a lot of reasons why the chemistry of molecules must be understood before we can better understand the behavior of chemicals within a highly interactive environmental setting. These chemicals are typically influenced by many of the chemicals and surfaces they come in contact with within the natural environmental setting. Chemicals that are suspended or dissolved in water rich settings behave differently than those that are percolating through soil, across solid rock surfaces, coming in contact with everything from the leftovers of plant and animal detritus on the soil surface to the acidic limestone or chalk located close to a new source clean water. Due to their low boiling points and evaporation rates, the smallest or lightest of organic waste products may never reach the lower layers fo the soil. The entrapment of still other chemicals within the food chain and ultimately between the layers of river beds provide us with yet another feature of environmentally stored chemicals that is hard to take into account when reviewing sites where these chemicals are released.
Brian Altonen, MPH, MS 