Dioxin: A Threshold Carcinogen

All substances are poisons; there is none which is
not a poison. The right dose differentiates a
poison from a remedy.
Paracelsus
1493 - 1541

Introduction

Paracelsus

The Swiss alchemist Paracelsus, born one year after Columbus arrived in the New World, is known as the father of toxicology, the science of poisons. It is likely that dioxin, a family of variably toxic chemical compounds unknown in the time of Paracelsus, would have been of interest to this man of science. Although it was generated in heating and cooking fires in homes throughout Europe in his day, Paracelsus spent his life unaware of dioxin. Had he been granted a glimpse into the future, however, he might have been intrigued by the current U.S. debate over dioxin's toxicity properties.

What is Dioxin?

Not just one substance, "dioxin" usually refers to a complex family of 17 chlorinated organic compounds of highly variable toxicity. Dioxin forms as mixtures of its family member compounds. Some members of the dioxin family are as much as 10,000 times less toxic than the most toxic ones.

No one manufactures dioxin intentionally; it is a trace byproduct of many industrial processes, especially those involving combustion. Dioxin forms naturally when organic matter burns, so forest fires, fireplaces, wood stoves and even volcanoes are all dioxin sources. It is a sure bet that human beings have always been exposed to these compounds. We cannot banish dioxin from the Earth any more than we can halt the lightening that strikes trees and sets forests ablaze.

Dioxin Levels Are Declining in Emissions, Sediments, Foods and Human Tissue

The good news about dioxin is that levels are falling in every medium examined. Using U.S. Environmental Protection Agency (EPA) data and estimates based on new pollution control standards, we can state that total dioxin emissions from all EPA-quantified sources have declined by 92 percent from 1987 levels. Figure 1 demonstrates parallel dioxin declines in lake sediments, foods and human tissue.

* 1 pg = 1 picogram (one-trillionth of a gram, 0.000000000001 g) 1 g = 1 gram (0.0022 lb.)
# This value is treated here as an outlier.
^ Human tissue dioxin level data are virtually unavailable prior to the early 1970s.

[These graphics are based on: Hagenmeier and Walczok (1996), Ferrario et al., (1998) and Lorber (2002). Sediment core samples reflect dioxin in the environment averaged over a time span. Food samples are retrieved from museums or other storage. The 1998 dioxin level in food is based on data tabulated in Institute of Medicine of the National Academies, Dioxins and Dioxin-like Compounds in the Food Supply: Strategies to Decrease Exposure (2003). Tissue data are human blood and fat.]

Human Exposure to Dioxin

According to the U.S. Interagency Working Group on Dioxin, more than 95 percent of human exposure to dioxin originates with the diet. Dioxin accumulates in the fatty components of meat and dairy products and then in human fatty tissue when these foods are consumed. Dioxin is eliminated at a rate determined by the amount of dioxin in the body-the higher the dioxin level in the body, the faster dioxin is eliminated. By following the general public health recommendation of the U.S. Centers for Disease Control and Prevention (CDC) to limit one's intake of fatty foods, it is possible to simultaneously reduce dioxin intake.

People today are exposed to significantly less dioxin than at any time in the past several decades. The CDC's July, 2005 Third National Report on Human Exposure to Environmental Chemicals affirms that dioxin levels in blood are very low and that these levels have declined by more than 80 percent since the 1980s.

The pie chart below illustrates a best estimate of the distribution of dioxin emission sources in the U.S. in 2004. While EPA does not include forest fires in its dioxin source inventories, the pie chart does include this source, the magnitude of which was calculated based on available forest fire statistics and forest fire dioxin emission factors. Given the potential for forest fires to comprise such a major source of dioxin, it is critical to include this source in any discussion of dioxin sources.

*With the exception of forest fire data, dioxin emissions source data are based on EPA projections for 2002/4, assuming full compliance with regulatory levels and the closure of a copper smelter (personal communication, Dwain Winters, US EPA, 9-9-02). #The dioxin contribution from forest fires was calculated using National Interagency Fire Center acreage burned in year 2004 wildland fires; an emission factor of 20 ng-TEQ/kg biomass burned [Gullett and Touati (2003)]; and a biomass consumption rate of 9.43 metric tons/acre in areas consumed by wildfires from Ward et al. (1976), as cited in the EPA Draft Dioxin Reassessment (September, 2000).

Threshold Effects

Paracelsus laid the foundation of toxicology with his famous observation quoted at the beginning of this article, and frequently repeated in the abridged version, "The dose makes the poison." Proof of this is not hard to find. We must drink a certain amount of water to stay alive, for example, but it is possible to drink so much water that we dilute our salt levels to dangerously low levels. We must expose our skin to sunlight in order for our bodies to manufacture vitamin D, but too much sunlight can induce painful sunburn and, worse, skin cancer. The critical point at which an exposure becomes harmful is called a threshold exposure. Armed with the knowledge of threshold exposure levels, it is possible to evaluate risk intelligently and manage risk by maintaining exposures under the threshold.

Modern toxicology tells us that for all carcinogens that do not directly damage DNA, there is a threshold level of exposure, or dose, below which no cancer results. Such substances, that are only carcinogenic after a certain level of exposure is achieved, are called threshold carcinogens. The difference between these two types of carcinogens is illustrated in Figure 3.

Cancer Response		Cancer Response
	Dose Non-threshold carcinogen: A cancer response can theoretically occur with the first molecule of exposure.	Figure 3	Dose Threshold carcinogen: No cancer response occurs until a threshold dose level is attained.

Dioxin's Mode of Action

EPA makes the conservative assumption that potential carcinogens can cause an increased risk of cancer no matter how small the dose. This assumption is loosely based on early theories that assumed all cancers are caused by direct toxicity to DNA, or "genotoxicity," and that even an exposure to a single molecule could cause cancer. Dioxin, however, has been shown by researchers to be non-genotoxic-non-toxic to the DNA found in genes. How then, does dioxin "act" in the human body to produce cancer?

Certain cells of mammals, such as liver cells, contain a large molecule called an aryl hydrocarbon receptor (AhR), which can be thought of as shaped like a pocket. Some compounds foreign to the body, such as dioxin, fit snugly into this pocket. Once in the pocket, dioxin activates the AhR and the whole unit can travel to the cell nucleus which contains an organism's genes. Once in the nucleus, the unit may either activate or suppress specific genes that control the normal cell life cycle. For example, certain cells may begin to grow preferentially, or other cells may not die appropriately, as normal cells do. It is important to note that gene suppression or activation is not the same as DNA damage.

Cancer is a complex, multi-stage process. If the AhR-dioxin unit is present at high enough levels for a long enough time in a cell nucleus, it can "encourage" or promote the cancerous development of cells that are already on the pathway to developing cancer. However, scientists have not determined the actual mechanism by which dioxin promotes the development of cancer.

Since the late 19th century, scientists have known that the interactions of foreign compounds with receptor molecules in the body are governed by the Law of Mass Action. Generally speaking, this law holds that the higher the quantities of reacting substances, the faster the reactions will occur. In the case of dioxin in the human body, the Law of Mass Action tells us that the toxic effect of dioxin is proportional to the level of "filled pockets" of AhR with dioxin. Studies show that for a cancer response to be activated, there must be a critical build-up, or threshold quantity, of these "filled pockets." Following that critical build-up, the cancer response increases, but it may not increase linearly. Complex factors interact at the cell level to likely produce a curved, non-linear cancer response similar to the threshold carcinogen graph shown in Figure 3.

Threshold Dose-Response

The dioxin cancer threshold dose-response relationship can be loosely analogized to the relationship between the build-up of antibodies in the human body resulting from exposure to food allergens and the eventual manifestation of a food allergy. In susceptible individuals, certain foods act as allergens, provoking the immune system to produce antibodies. "Sensitization" occurs over a period of time as the individual's antibody level rises. At some point, a threshold value of antibody level is reached and the individual begins to experience food allergy symptoms.

Figure 4

Surmising a threshold type of dose-response relationship for dioxin cancer effects, several world public health bodies have decided to focus their attention on dioxin's non-cancer health effects as more sensitive indicators of exposure. The U.S. Agency for Toxic Substances and Disease Registry (ATSDR), the Joint United Nations Food and Agriculture Organization/World Health Organization Expert Committee on Food Additives (JECFA) and the European Commission Scientific Committee on Food (EC SCF) have based exposure guidelines for dioxin on sensitive noncancer endpoints. Nevertheless, EPA has chosen to characterize dioxin as a linear, non-threshold carcinogen.

In a recent experimental study, a team led by Dr. Nigel J. Walker examined dose additive cancer effects in rodents receiving three different dioxin-like compounds and mixtures of these compounds. Dose-response curves for all cancers studied were characterized as "highly non linear"¹ .

Dioxin Public Policy: What's Best for Public Health?

At first blush, EPA's intention to label dioxin a linear, non-threshold carcinogen might seem to be admirably protective of public health. But, in fact, this decision conflicts with EPA's own guidelines for cancer risk assessment which call for setting of a reference dose when nonlinearity is observed. A reference dose is an estimate of a daily exposure that is not likely to cause harmful effects over the course of a lifetime.

The EPA's newly released cancer guidelines state:

When adequate data on mode of action provide
sufficient evidence to support a nonlinear mode of
action for the general population and/or any
subpopulations of concern, a different approach-
a reference dose/reference concentration that
assumes that nonlinearity-is used.

Yet, EPA has not established a reference dose for dioxin and holds to the linear, non-threshold characterization, even though studies indicate the existence of a dioxin exposure below which cancer risk is negligible.

It may be argued that EPA's choice to cling to a linear non-threshold dose-response relationship for dioxin could result in a net loss to public health as resources, needed for better substantiated risks, are diverted to dioxin.

Dr. Tuomisto² writes:

Using upper bound estimates is not risk
assessment, it is a political decision maximizing
the risk in order to be precautionary in case of
error. To be successful, however, this assumes
that no other risks are involved, and we can make
our decision in isolation. If avoiding one risk leads
to an increase in some other risk, then our
precautionary logic does not work.

Conclusion

As for all chemicals, the dioxin dose makes the poison. All evidence points to the fact that dioxin is a threshold carcinogen. In the best interest of public health, and with limited public funds, it would be prudent to recognize this threshold, and regulate dioxin accordingly. Ultra-conservative risk assessments of environmental chemicals drain public and private resources without proportional benefit. Even worse, they channel attention away from more pressing needs.

Given a chance to communicate across the generations, no doubt Paracelsus would agree.

Endnotes

¹"Dose-additive carcinogenicity of a defined mixture of "dioxin-like compounds," Environmental Health Perspectives; Oct. 19, 2004, available at http://dx.doi.org/).
²Tuomisto, J. (2004). Does mechanistic understanding help in risk assessment-the example of dioxins. Deichmann Lecture ICTX Proceedings.