Dioxin: A Threshold Carcinogen
All substances are poisons; there is none
not a poison. The right dose differentiates a
poison from a remedy.
1493 - 1541
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's in a name?
"Dioxin" is a shortened version of the technical chemical
name given to some of the family member compounds. These
compounds contain two oxygen atoms in their chemical
structure, hence, "di" refers to "two" and "ox" refers
Chemical structure of 2,3,7,8-tetrachlorodibenzo-p-dioxin
(the numbers indicate the locations of chlorine atoms
in the molecule.)
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
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.
Figure 1: Trends in Dioxin in the
Environment and in 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
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,
A Finnish Case Study of Comparative
An enlightening example of comparative
risk assessment comes from Finland, where, according
to Dr. J. T. Tuomisto of the Finnish National Public
Health Institute, as much as 80 percent of dioxin exposure
comes from fish consumption. While reducing fish consumption
would reduce dioxin exposure in the population, it would
also yield an unintended consequence: an increase in
the death rate due to cardiovascular disease.
In Finland, fish is the main source of
omega-3 fatty acids, nutritional components that have
been shown to decrease cardiovascular deaths. Tuomisto
estimated the net loss of life in Finland if farmed
salmon consumption were limited to once a month or less,
based on the recommendation put forth by the U.S. EPA
(2000). He estimated that, with limited farmed salmon
consumption, the estimated cancer risk is reduced by
approximately 50 deaths. But, fish consumption is thought
to prevent 30,000 cardiac deaths annually. Limited fish
consumption would result in losing some, but not all,
of this benefit. Tuomisto predicted 7,500 extra deaths
per year due from cardiovascular causes if limited fish
consumption were practiced in Finland.
Comparing 50 extra estimated (cancer)
deaths per year to 7,500 extra (cardiovascular) deaths
per year should leave no doubt in anyone's mind that
fish consumption in Finland should not be limited.
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.
Non-threshold carcinogen: A cancer response can theoretically
occur with the first molecule of exposure.
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.
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.
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
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
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.
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.
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.