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Environmental Exposures

Historically, national regulatory agencies have sought to identify and limit our exposures to carcinogens (i.e., individual agents that can cause cancer). However, as the decades have passed, we have come to realize that relatively few chemicals are complete carcinogens (i.e., have the potential to enable all of these hallmarks on their own). But it is now known that many of the hallmark mechanisms of cancer can be independently enabled by individual chemicals, and that realization changes everything.

While the identification of complete carcinogens will always be an important activity, we now also need to be seriously concerned about the ways in which exposures to combinations of disruptive, but otherwise non-carcinogenic, environmental agents are able to act in concert with one another to instigate the disease. In other words, the hallmarks of cancer framework illustrates that we need to also be concerned about cumulative exposures to chemicals that can disrupt the cellular machinery that is associated with any number of these hallmarks, because a multitude of exposures (each enabling a number of hallmarks) could easily instigate cancer. Contemplating this possibility requires a much more nuanced appreciation of the complexity of the disease (from a regulatory perspective), but it is an issue that must be quickly addressed if we want to ensure that the public is protected from environmental exposures that can cause cancer.

Unfortunately, regulators are currently lagging behind the science in this regard, and most countries simply do not have assessment policies/practices that adequately address the carcinogenic contributions of the many individual chemical exposures that we face. For example, The Environmental Protection Agency in the United Stated and Health Canada's Pest Management Regulatory Agency are both required by law to consider cumulative toxicological effects of chemicals that are registered for uses in ways that expose the population and potentially place them at risk. And from a carcinogenicity perspective, both agencies are therefore required to consider the cumulative effects of chemicals that are known to share common modes of (carcinogenic) action. However, in practice, this is rarely done.

Genetic Instability

For example, cancer is a disease, with many genes in many diverse pathways that are typically involved in its multistep process of enablement, and it is widely accepted that the accumulation of mutations that promote the immortalization of proliferating cells (i.e., activate oncogenes) and disrupt the mechanisms which should stop this from occurring (i.e., disable tumor suppressor genes) can cause cancer. Genetic instability itself is therefore a mode of (carcinogenic) action that has the potential to promote unscheduled genetic alterations and cause cancer. And since the genome controls all aspects of cellular function, random genetic damage can potentially enable any of the other modes of action (as illustrated in the schematic diagram below).

Both the US EPA and Health Canada’s PMRA know that chemicals that cause mutations can cause cancer, so both agencies routinely assess chemicals for their ability to cause cellular-level mutations. However, when it comes time to develop an risk-assessment model and establish safe levels of exposure for any given chemical that has mutagenic potential, the agencies generally do not consider the cumulative effect that the exposure will have when combined with the many other chemicals that have mutagenic potential that have already been registered/approved. In other words, although both agencies have carefully documented the mutagenic potential of many registered chemicals, risk assessments of these chemicals typically do not consider the cumulative effects of population-level exposures to all of them combined.

Furthermore, this mode of action also encompasses disrupted DNA repair systems. Yet neither agency assesses the cumulative effects of exposures to mixtures of chemicals that can damage DNA on the one hand, and simultaneously damage the ability of cells to repair that damage on the other hand. So, for example, ethylenediaminetetraacetic acid or EDTA is found in Ferric sodium EDTA and used as a molluscicide to control slugs and snails on a variety of food crops, and it is also widely used as an additive in personal care products, food products and medicinal products. Yet EDTA is a disruptive chemical that inhibits DNA repair. When EDTA is combined with chemical mutagens, it increases the frequency of mutations, which makes it a potentially important contributor to genetic instability. Yet the cumulative effects of this sort of additional disruption are simply not factored into the risk assessments generated by either regulatory agency.

It is also well known that mitochondrial damage in the cell can cause reactive oxygen species to be generated causing oxidative stress and DNA damage which can also contribute to genetic instability. Yet this is another source of genetic instability that is often ignored. For example, Paraquat is a herbicide used in Canada and the United States on a variety of food crops and it is a well-established inducer of oxidative stress which make it a direct contributor to genetic instability. So its cumulative effects when combined with other chemicals that contribute to genetic instability should be considered in any risk assessment calculations (i.e., given that genetic instability is an important mode of action that has the potential to instigate cancer), but again this is not something that is done.

Other Modes of (Carcinogenic) Action

Note that the example above considers genetic instability, which is only one mode of (carcinogenic) action. Yet it should be obvious that risk assessment calculations of combined exposures to low doses of chemicals should factor in the cumulative effects of chemicals that contribute to any/all of the known modes of (carcinogenic) action. Many chemicals have been approved for uses that expose the population, and the contributions that these chemicals have on the various modes of (carcinogenic) action are often well documented, but regulators are simply not factoring the cumulative effects of these chemicals into their risk assessment activities. A small sampling of examples that fit this description are shown in the table below.

In other words, the current methods for carcinogenicity determination would be fine if we were only looking for individual chemicals that are carcinogenic on their own. But in the real world, we are being exposed to mixtures of these chemicals, so the disruptive actions of chemicals that act on any/all of the modes of (carcinogenic) action are equally as important (even if these same chemicals do not cause cancer on their own when tested in isolation).

At a minimum, we need to place an emphasis on the importance of the natural biological defense mechanisms that should stop cancer and put safeguards in place to guard against environmental exposures that disrupt these capabilities. For example, environmental exposures that disable or suppress DNA repair, proper stress-axis function (inflammation suppression), the cellular mechanisms that recognizes anti-growth signalling (e.g., cell-cycle checkpoint signalling), the cellular self-destruct mechanism (apoptosis), the cellular copy-limit (senescence) and various key components of the immune system need to be identified, regulated and minimized or eliminated to the extent possible.