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Low-dose chemical mixtures may trigger cancers

Date Added to website 18 July 2015


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Low-dose chemical mixtures may trigger cancers
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[This is an influential review written by a task force of 173 scientists from many countries which examines the links between 85 common chemicals (in the environment and in food supplies) and 11 hallmark phenotypes of cancer. The authors conclude that only 15% of the chemicals showed evidence of a dose-response threshold, but that 59% exerted low-dose effects -- that is, they worked in combination with other chemicals to create pathways leading to cancers. This is of vast importance, since chemical companies and regulators generally insist of examining individual chemicals in isolation with a view to declaring them "safe for human consumption" at specified levels. The term "acceptable daily intake" is bandied about all the time, implying that if people are exposed to levels below the ADI they are perfectly safe. Since it now appears that many chemicals have effects that are not dose-dependent, it looks as if a major rethink about human exposures to environmental toxins will have to be undertaken. It is also pleasing to see that combinatorial effects of toxins are now looked at seriously. We hope that the members of the GMO Panel at EFSA will read this research, since they steadfastly refuse to accept that there can be combinatorial or synergistic effects when various toxins are brought together in stacked GMO "events". Put this together with the recent WHO Panel report declaring glyphosate to be a "probable human carcinogen" and we see the beginnings of a new era of "toxic awareness."]

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Review: "Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead."
William H.Goodson et al
Carcinogenesis, 2015, Vol. 36, Supplement 1, S254–S296
doi:10.1093/carcin/bgv039

http://carcin.oxfordjournals.org/content/36/Suppl_1/S254.full.pdf

Abstract
Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the
World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

Summary/Conclusions
For several decades, there has been a concerted effort to identify individual chemicals and other agents that are arcinogenic. At the same time, however, little has been done to determine whether or not chronic lifetime exposures to mixtures of noncarcinogenic chemicals in the environment (at low-dose levels) have carcinogenic potential. Many chemicals are known to accumulate in bodily tissues over time, but little is known about their combined effects at a mechanistic level and their impact on cancer-related mechanisms and carcinogenesis. In this project, teams of cancer biologists worked with researchers in the field of environmental health for the very first time to explore this possibility.

Teams that reviewed these cancer-related phenotypes (i.e. genetic instability, tumor-promoting inflammation, sustained proliferative signaling, insensitivity to antigrowth signals, resistance to cell death, angiogenesis, tissue invasion and metastasis, the tumor microenvironment and avoiding immune destruction) readily identified individual (non-carcinogenic) chemicals that are ubiquitous in the environment that have some potential to act on key/priority functional targets in each of these domains. In contrast, the teams focused on replicative immortality and dysregulated metabolism found examples of chemicals to consider but noted a significant lack of useful toxicological research in these areas.

In total, 85 examples of environmental chemicals were reviewed as prototypical disruptors (for specific actions on key pathways/mechanisms that are important for carcinogenesis) and 59% of them (i.e. 50/85) were found to exert LDE (at levels that are deemed relevant given the background levels of exposure that exist in the environment) with 15 of the 50 demonstrating their LDE in a non-linear dose-response pattern. Only 15% of the chemicals reviewed (i.e. 13/85) were found to have a dose-response threshold and the remaining 26% (i.e. 22/85) were categorized as ‘unknown’ due to a lack of dose-response information. Cross-hallmark effects for all target sites for disruption and for all chemicals were found, but the evidence supporting these results varied considerably in strength and in context. A number of the teams also cited relevant in-utero exposure studies in their reviews and presented data on transgenerational effects related to different aspects of the disease (e.g. inflammation, immune evasion and so on). These examples raise intriguing possibilities about vulnerabilities at the population level, and the contributions that in-utero and early life exposures to mixtures of those chemicals might make towards cancer susceptibility. Therefore, current regulations in many countries (that consider only the cumulative effects of exposures to individual carcinogens that act via a common sequence of key events and processes on a common target/tissue to produce cancer) should be revisited. Our current understanding of the biology of cancer suggests that the cumulative effects of (non-carcinogenic) chemicals acting on different pathways that are relevant to cancer, and on a variety of cancer-relevant systems, organs, tissues and cells could conspire to produce carcinogenic synergies that will be overlooked using current risk assessment methods. Cumulative risk assessment methods that are based on ‘common mechanisms of toxicity’ or common ‘modes of action’ may therefore be underestimating cancer-related risks. In-utero and early life exposures, transgenerational effects and the interplay between the low-dose mechanistic effects of chemical mixtures in the environment and the vulnerabilities of subpopulations who are predisposed to cancer (i.e. via genetics or other influences) must also be considered. Current policies and practices do not adequately address these issues and should therefore be revisited if regulatory agencies hope to better understand and assess these risks. Finally, given the long latency period in most cancers, early detection to cancer is key so an improved understanding of the biology within originating tissues (during the latency period) would be very helpful. If we can use the heuristic presented in this review to better assess the combined effects of common exposures to chemical mixtures in the environment, it will help us improve our understanding of carcinogenesis and identify exogenous triggers and enabling factors (in utero and during this important latency period), all of which will be key for the development of effective strategies for prevention and early detection.

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Exposure to mixture of common chemicals may trigger cancer, scientists find
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http://www.theguardian.com/science/2015/jun/23/exposure-to-mixture-of-chemicals-may-trigger-cancer-scientists-find

One in five cancers may be caused when common chemicals – deemed safe on their own – blend lethally inside the human body, study reveals

Chemicals deemed safe to humans may blend lethally together inside the human body to cause cancer, a report says.

Researchers, including New Zealand scientist Dr Linda Gulliver, have released findings into possible links between common chemicals and the development of cancer.

Their results, published in the journal Carcinogenesis, show mixtures of chemicals used in our environment may be acting in concert with each other inside the body to trigger the disease.

Gulliver, from Otago University’s faculty of medicine, says on the back of the findings of the Halifax Project, “considerable attention” needs to be given to investigating the concerning links.

A high-profile taskforce was formed in 2013 by the international organisation Getting to Know Cancer, which was concerned that cancer research was focused primarily on the role of heritable and lifestyle factors as triggers.

This is despite evidence that as many as one in five cancers may be caused by chemical exposures in the environment that are not related to personal lifestyle choices.

Chemicals are tested for carcinogenic links, but only one at a time, leaving questions around the possibility that a fusion of these chemicals may instead be causing cancer.

The taskforce of 174 scientists in 28 countries investigated 85 prototypic chemicals that were not considered to be carcinogenic to humans, and they reviewed their effects against a long list of mechanisms that are important for cancer development.

Working in teams that focused on various hallmarks of cancer, the group found that 50 of those chemicals examined supported key cancer-related mechanisms at levels at which humans are routinely exposed.

The finding supports the idea that chemicals may be capable of acting in concert with one another to cause cancer, even though low-level exposures to these chemicals individually might not be carcinogenic.

Lead researcher William Goodson III, from San Francisco’s California Pacific Medical Center, said his results show one-at-a-time testing is out of date and must be modernised.

“Every day we are exposed to an environmental ‘chemical soup’, so we need testing that evaluates the effects of our ongoing exposure to these chemical mixtures,” he said.