- Polychlorinated dibenzo-p-dioxins (PCDDs), or simply dioxins. PCDDs are derivatives of dibenzo-p-dioxin. There are 75 PCDD congeners, differing in the number and location of chlorine atoms, and seven of them are especially toxic, the most dangerous being 2,3,7,8-Tetrachlorodibenzodioxin (TCDD)
- Polychlorinated dibenzofurans (PCDFs), or furans. PCDFs are derivatives of dibenzofuran. There are 135 isomers, ten have dioxin-like properties.
- Polychlorinated/polybrominated biphenyls (PCBs/PBBs), derived from biphenyl, of which twelve are "dioxin-like". Under certain conditions PCBs may form dibenzofurans/dioxins through partial oxidation.
- Finally, dioxin may refer to 1,4-Dioxin proper, the basic chemical unit of the more complex dioxins. This simple compound is not persistent and has no PCDD-like toxicity.
In reference to their importance as environmental toxicants the term dioxins is used almost exclusively to refer to the sum of compounds (as TEQ) from the above groups which demonstrate the same specific toxic mode of action associated with TCDD. These include 17 PCDD/Fs and 12 PCBs. Incidents of contamination with PCBs are also often reported as dioxin contamination incidents since it is this toxic characteristic which is of most public and regulatory concern.
Toxicity
Mechanism of toxicity
The toxic effects of dioxins are measured in fractional equivalencies of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), the most toxic and best studied member of its class (see TCDD
for more detailed description of the mechanism). The toxicity is
mediated through the interaction with a specific intracellular protein,
the aryl hydrocarbon (AH) receptor, a transcriptional enhancer, affecting a number of other regulatory proteins. This receptor is a transcription factor which is involved in expression of many genes. TCDD binding to the AH receptor induces the cytochrome P450 1A class of enzymes which function to break down toxic compounds, e.g., carcinogenic polycyclic hydrocarbons such as benzo(a)pyrene (but making many of them more toxic in the process).
While the affinity of dioxins and related industrial toxicants to
this receptor may not fully explain all their toxic effects including
immunotoxicity, endocrine effects and tumor promotion, toxic responses appear to be typically dose-dependent within certain concentration ranges. A multiphasic dose-response relationship has also been reported, leading to uncertainty and debate about the true role of dioxins in cancer rates.
The endocrine disrupting activity of dioxins is thought to occur
as a down-stream function of AH receptor activation, with thyroid status
in particular being a sensitive marker of exposure. It is important to
note that TCDD, along with the other PCDDs, PCDFs and dioxin-like
coplanar PCBs are not direct agonists or antagonists of hormones, and
are not active in assays which directly screen for these activities such
as ER-CALUX and AR-CALUX. These compounds have also not been shown to have any direct mutagenic or genotoxic activity. Their main action in causing cancer is cancer promotion. A mixture of PCBs such as Aroclor may contain PCB compounds which are known estrogen agonists,
but on the other hand are not classified as dioxin-like in terms of
toxicity. Mutagenic effects have been established for some lower
chlorinated chemicals such as 3-chlorodibenzofuran, which is neither
persistent nor an AH receptor agonist.
Toxicity in animals
The
symptoms reported to be associated with dioxin toxicity in animal
studies are incredibly wide-ranging, both in the scope of the biological
systems affected and in the range of dosage needed to bring these
about. Acute effects of single high dose dioxin exposure include wasting syndrome, and typically a delayed death of the animal in 1 to 6 weeks. By far most toxicity studies have been performed using 2,3,7,8-tetrachlorodibenzo-p-dioxin.
The LD50
of TCDD varies wildly between species and even strains of the same
species, with the most notable disparity being between the seemingly
similar species of hamster and guinea pig. The oral LD50 for guinea pigs is as low as 0.5 to 2 μg/kg body weight, whereas the oral LD50 for hamsters can be as high as 1 to 5 mg/kg body weight. Even between different mouse or rat strains there may be tenfold to thousandfold differences in acute toxicity. Many pathological findings are seen in the liver, thymus and other organs.
Some chronic and sub-chronic exposures can be harmful at much
lower levels, especially at particular developmental stages including foetal, neonatal and pubescent stages. Well established developmental effects are cleft palate, hydronephrosis, disturbances in tooth development and sexual development as well as endocrine effects.
Human toxicity
Dioxins
have been considered highly toxic and able to cause reproductive and
developmental problems, damage the immune system, interfere with
hormones and also cause cancer.
This is based on animal studies. The best proven is chloracne. Even in poisonings with huge doses of TCDD, the only persistent effects after the initial malaise have been chloracne and amenorrhea. In occupational settings many symptoms have been seen, but exposures have always been to a multitude of chemicals including chlorophenols, chlorophenoxy acid herbicides, and solvents. Therefore, proof of dioxins as causative factors has been difficult. The suspected effects in adults are liver damage, and alterations in heme metabolism, serum lipid levels, thyroid functions, as well as diabetes and immunological effects.
In line with animal studies, developmental effects may be much
more important than effects in adults. These include disturbances of tooth development, and of sexual development. An example of the variation in responses is clearly seen in a study following the Seveso disaster indicating that sperm
count and motility were affected in different ways in exposed males,
depending on whether they were exposed before, during or after puberty.
Intrauterine exposure to dioxins and dioxin-like compounds as an environmental toxin in pregnancy has subtle effects on the child later in life that include changes in liver function, thyroid hormone levels, white blood cell levels, and decreased performance in tests of learning and intelligence.
Exposure to dioxins can happen in a number of ways, most often as
by-products of industrial waste. However, dioxins can result from
natural processes including volcanic eruptions and forest fires, and
manufacturing processes such as smelting, chlorine bleaching of paper pulp, and the creation of some herbicides and pesticides.
Even at levels 100X lower than those associated with its cancer causing
effects, the presence of dioxin can cause immune system damage, severe
reproductive and developmental problems, and interference with
regulatory hormones.
The Endometriosis Research Center (ERC) has testified before the
California State Legislature concerning Assembly Bill 2820 [Cardoza,
D-Merced] that, "feminine hygiene products (i.e. tampons) do indeed test
positive for Dioxin. Dioxin, in turn, is a well-documented catalyst for
Endometriosis - and the effects of Dioxin are cumulative; able to be
measured as much as 20 or 30 years after exposure."
The ERC also references an independent study that found, in an
assessment of four brands of tampons and four brands of baby diapers,
dioxins "were present at detectable concentrations in all samples." The
presence of this toxin in tampons may be linked to endometriosis because
dioxins last a long time in the body; they are chemically stable and
can be absorbed by fat tissue, where they are then stored in the body.
Their half-life in the body is estimated to be 7 to 11 years.
Carcinogenicity
Dioxins are well established carcinogens in animal studies, although the precise mechanistic role is not clear. Dioxins are not mutagenic or genotoxic. The United States Environmental Protection Agency
has categorised dioxin, and the mixture of substances associated with
sources of dioxin toxicity as a "likely human carcinogen". The International Agency for Research on Cancer
has classified TCDD as a human carcinogen (class 1) on the basis of
clear animal carcinogenicity and limited human data, but was not able to
classify other dioxins.
It is thought that the presence of dioxin can accelerate the formation
of tumours and adversely affect the normal mechanisms for inhibiting
tumour growth, without actually instigating the carcinogenic event.
As with all toxic endpoints of dioxin, a clear dose-response
relationship is very difficult to establish. After accidental or high
occupational exposures there is evidence on human carcinogenicity. There is much controversy especially on cancer risk at low population levels of dioxins. Among fishermen with high dioxin concentrations in their bodies, cancer deaths were decreased rather than increased. Some researchers have also proposed that dioxin induces cancer progression through a very different mitochondrial pathway.
Risk assessment
The
uncertainty and variability in the dose-response relationship of
dioxins in terms of their toxicity, as well as the ability of dioxins to
bioaccumulate mean that the tolerable daily intake (TDI) of dioxin has been set very low, 1-4 pg/kg body weight per day, i.e. 7x10−11 to 2.8x10−10g
per 70-kg person per day, to allow for this uncertainty and ensure
public safety in all instances. Specifically, the TDI has been assessed
based on the safety of children born to mothers exposed all their
lifetime prior to pregnancy to such a daily intake of dioxins.
It is likely that the TDI for other population groups could be somewhat
higher. The most important cause for differences in different
assessments is carcinogenicity. If the dose-response of TCDD in causing
cancer is linear, it might be a true risk. If the dose-response is of a
threshold-type or J-shape, there is little or no risk at the present
concentrations. Understanding the mechanisms of toxicity better is hoped
to increase the reliability of risk assessment.
Controversy
Greenpeace and some other environmental groups have called for the chlorine industry to be phased out.
However, chlorine industry supporters say that "banning chlorine would
mean that millions of people in the third world would die from want of
disinfected water". (Although critics point out the existence of alternative water disinfection methods.)
Sharon Beder
and others have argued that the dioxin controversy has been very
political and that large companies have tried to play down the
seriousness of the problems of dioxin. The companies involved have often said that the campaign against dioxin is based on "fear and emotion" and not on science.
In 2008, Chile experienced a pork crisis
caused by high dioxin concentrations in their pork exports. The
contamination was found to be due to zinc oxide used in pork feed, and
caused reputational and financial losses for the country, as well as
leading to the introduction of new food safety regulations.
Human intake and levels
Most
intake of dioxin-like chemicals is from food of animal origin: meat,
dairy products, or fish predominate, depending on the country. The daily intake of dioxins and dioxin-like PCBs as TEQ is of the order of 100 pg/day, i.e. 1-2 pg/kg/day.
In many countries both the absolute and relative significance of dairy
products and meat have decreased due to strict emission controls, and
brought about the decrease of total intake. E.g. in the United Kingdom
the total intake of PCDD/F in 1982 was 239 pg/day and in 2001 only 21
pg/day (WHO-TEQ).
Since the half-lives are very long (for e.g. TCDD 7–8 years), the body
burden will increase almost over the whole lifetime. Therefore, the
concentrations may increase five- to tenfold from age 20 to age 60.
For the same reason, short term higher intake such as after food
contamination incidents, is not crucial unless it is extremely high or
lasts for several months or years.
The highest body burdens were found in Western Europe in the 1970s and early 1980s, and the trends have been similar in the U.S. The most useful measure of time trends is concentration in breast milk measured over decades.
In many countries the concentrations have decreased to about one tenth
of those in the 1970s, and the total TEQ concentrations are now of the
order of 10-30 pg/g fat (please note the units, pg/g is the same as ng/kg, or the non-standard expression ppt used sometimes in America). The decrease is due to strict emission controls and also to the control of concentrations in food.
In the U.S. young adult female population (age group 20-39), the
concentration was 9.7 pg/g lipid in 2001-2002 (geometric mean).
Certain professions such as subsistence fishermen in some areas are exposed to exceptionally high amounts of dioxins and related substances. This along with high industrial exposures may be the most valuable source of information on the health risks of dioxins.
Uses
Dioxins have
no common uses. They are manufactured on a small scale for chemical and
toxicological research, but mostly exist as by-products of industrial processes such as bleaching paper pulp, pesticide manufacture, and combustion processes such as waste incineration. The defoliant Agent Orange contained dioxins. The production and use of dioxins was banned by the Stockholm Convention in 2001.
Sources
Environmental sources
PCB-compounds, always containing low concentrations of dioxin-like PCBs and PCDFs, were synthesized for various technical purposes.
They have entered the environment through accidents such as fires or
leaks from transformers or heat exchangers, or from PCB-containing
products in landfills or during incineration. Because PCBs are somewhat
volatile, they have also been transported long distances by air leading
to global distribution including the Arctic.
PCDD/F-compounds were never synthesized for any purpose, except for small quantities for scientific research. Small amounts of PCDD/Fs are formed whenever organics, oxygen and chlorine are available at suitable temperatures.
This is augmented by metal catalysts such as copper. The optimal
temperature range is 400 °C to 700 °C. This means that formation is
highest when organic material is burned in less-than-optimal conditions
such as open fires, building fires, domestic fireplaces, and poorly
operated and/or designed solid waste incinerators. Historically, municipal and medical waste incineration was the most important source of PCDD/Fs.
Other sources of PCDD/F include:
- Metal smelting and refining
- Chlorine bleaching of pulp and paper - historically important source of PCDD/Fs to waterways.
- Synthesis side products of several chemicals, especially PCBs, chlorophenols, chlorophenoxy acid herbicides and hexachlorophene.
- Uncontrolled combustion, particularly open burning of waste ("backyard barrel burning"), accidental fires, wildfires.
- (Historical) Engines using leaded fuel, which contained the additives 1,2-Dichloroethane and 1,2-Dibromoethane.
In waste incineration
Improvements and changes have been made to nearly all industrial
sources to reduce PCDD/F production. In waste incineration, large
amounts of publicity and concern surrounded dioxin-like compounds during
the 1980s-1990s continues to pervade the public consciousness,
especially when new incineration and waste-to-energy
facilities are proposed. As a result of these concerns, incineration
processes have been improved with increased combustion temperatures
(over 1000 °C), better furnace control, and sufficient residence time
allotted to ensure complete oxidation of organic compounds. Ideally, an
incineration process oxidizes all carbon to CO2 and converts all chlorine to HCl
or inorganic chlorides prior to the gases passing through the
temperature window of 700-400 °C where PCDD/F formation is possible.
These substances cannot easily form organic compounds, and HCl is easily
and safely neutralized in the scrubber while CO2 is vented to the atmosphere. Inorganic chlorides are incorporated into the ash.
Scrubber and particulate removal systems manage to capture most
of the PCDD/F which forms even in sophisticated incineration plants.
These PCDD/Fs are generally not destroyed but moved into the fly ash. Catalytic
systems have been designed which destroy vapor-phase PCDD/Fs at
relatively low temperatures. This technology is often combined with the baghouse or SCR system at the tail end of an incineration plant.
European Union limits for concentration of dioxin-like compounds in the discharged flue gas is 0.1 ng/Nm³ TEQ.
Both in Europe and in U.S.A.,
the emissions have decreased dramatically since the 1980s, by even 90%.
This has also led to decreases in human body burdens, which is neatly
demonstrated by the decrease of dioxin concentrations in breast milk.
With the substantial decrease of emissions from municipal waste
incinerators, other potentially large sources of dioxin-like compounds,
for example from forest and wild fires, have increased relative to
industrial sources. They are however not included in the total inventory due to uncertainties in available data.
Open burning of waste (backyard barrel burning) has not decreased
effectively, and in the U.S. it is now the most important source of
dioxins. Total U.S. annual emissions decreased from 14 kg in 1987 to
1.4 kg in 2000. However, backyard barrel burning decreased only modestly
from 0.6 kg to 0.5 kg, resulting in over one third of all dioxins in
the year 2000 from backyard burning alone.
Low concentrations of dioxins have been found in some soils
without any anthropogenic contamination. A puzzling case of milk
contamination was detected in Germany. The source was found to be kaolin
added to animal feed. Dioxins have been repeatedly detected in clays
from Europe and USA since 1996, with contamination of clay assumed to be
the result of ancient forest fires or similar natural events with
concentration of the PCDD/F during clay sedimentation.
Environmental persistence and bioaccumulation
All groups of dioxin-like compounds are persistent in the environment.
Very few soil microbes nor animals are able to break down effectively
the PCDD/Fs with lateral chlorines (positions 2,3,7, and 8).
This causes very slow elimination. However scientists at Martin Luther University
recently found that a type of bacteria Dehalococcoides CBDB1 can
extract the chlorine from dioxin compounds in the absence of oxygen.
Ultraviolet light is able to slowly break down these compounds.
Lipophilicity (tendency to seek for fat-like environments) and very poor
water solubility make these compounds move from water environment to
living organisms having lipid cell structures. This is called bioaccumulation.
Increase in chlorination increases both stability and lipophilicity.
The compounds with the very highest chlorine numbers (e.g.
octachlorodibenzo-p-dioxin) are, however, so poorly soluble that this
hinders their bioaccumulation. Bioaccumulation is followed by biomagnification.
Lipid-soluble compounds are first accumulated to microscopic organisms
such as phytoplankton (plankton of plant character, e.g. algae).
Phytoplankton is consumed by animal plankton, this by invertebrates such
as insects, these by small fish, and further by large fish and seals.
At every stage or trophic level,
the concentration is higher, because the persistent chemicals are not
"burned off" when the higher organism uses the fat of the prey organism
to produce energy.
Due to bioaccumulation and biomagnification, the species at the top of the trophic pyramid are most vulnerable to dioxin-like compounds. In Europe, the white-tailed eagle and some species of seals have approached extinction due to poisoning by persistent organic pollutants. Likewise, in America, the population of bald eagles declined because of POPs causing thinning of eggshells and other reproductive problems. Usually, the failure has been attributed mostly to DDT,
but dioxins are also a possible cause of reproductive effects. Both in
America and in Europe, many waterfowl have high concentrations of
dioxins, but usually not high enough to disturb their reproductive
success. Due to supplementary winter feeding and other measures also, the white-tailed eagle is recovering (see White-tailed eagle). Also, ringed seals in the Baltic Sea are recovering.
Humans are also at the top of the trophic pyramid, particularly
newborns. Exclusively breastfed newborns were estimated to be exposed to
a total of 800 pg TEQ/day, leading to an estimated body weight-based
dose of 242 pg TEQ/kg/day. Due to a multitude of food sources of adult humans exposure is much less averaging at 1 pg TEQ/kg-day, and dioxin concentrations in adults are much less at 10-100 pg/g, compared with 9000 to 340,000 pg/g (TEQ in lipid) in eagles or seals feeding almost exclusively on fish.
Because of different physicochemical properties, not all
congeners of dioxin-like compounds find their routes to human beings
equally well. Measured as TEQs, the dominant congeners in human tissues
are 2,3,7,8-TCDD, 1,2,3,7,8-PeCDD, 1,2,3,6,7,8-HxCDD and
2,3,4,7,8-PeCDF.
This is very different from most sources where hepta- and
octa-congeners may predominate. The WHO panel re-evaluating the TEF
values in 2005 expressed their concern that emissions should not be
uncritically measured as TEQs, because all congeners are not equally
important.
They stated that "when a human risk assessment is to be done from
abiotic matrices, factors such as fate, transport, and bioavailability
from each matrix be specifically considered".
All POPs are poorly water-soluble, especially dioxins. Therefore,
ground water contamination has not been a problem, even in cases of
severe contamination due to the main chemicals such as chlorophenols.
In surface waters, dioxins are bound to organic and inorganic particles.
Fate of dioxins in human body
The
same features causing persistence of dioxins in the environment, also
cause very slow elimination in humans and animals. Because of low water
solubility, kidneys are not able to secrete them in urine as such. They
should be metabolised to more water-soluble metabolites, but also
metabolism especially in humans is extremely slow. This results in
biological half-lives
of several years for all dioxins. That of TCDD is estimated to be 7 to 8
years, and for other PCDD/Fs from 1.4 to 13 years, PCDFs on average
slightly shorter than PCDDs.
Dioxins are absorbed well from the digestive tract, if they are dissolved in fats or oils (e.g. in fish or meat).
On the other hand, dioxins tend to adsorb tightly to soil particles,
and absorption may be quite low: 13.8% of the given dose of TEQs in
contaminated soil was absorbed.
In mammalian organisms, dioxins are found mostly in fat.
Concentrations in fat seem to be relatively similar, be it serum fat,
adipose tissue fat, or milk fat. This permits measuring dioxin burden by
analysing breast milk.
Initially, however, at least in laboratory animals, after a single
dose, high concentrations are found in the liver, but in a few days,
adipose tissue will predominate. In rat liver, however, high doses cause
induction of CYP1A2 enzyme, and this binds dioxins. Thus, depending on
the dose, the ratio of fat and liver tissue concentrations may vary
considerably in rodents.
Sources of human exposure
The most important source of human exposure is fatty food of animal origin (see Human intake, above), and breast milk.
There is much variation between different countries as to the most
important items. In U.S. and Central Europe, milk, dairy products and
meat have been by far the most important sources. In some countries,
notably in Finland and to some extent in Sweden, fish is important due
to contaminated Baltic fish and very low intake from any other sources. In most countries, a significant decrease of dioxin intake has occurred due to stricter controls during the last 20 years.
Historically occupational exposure to dioxins has been a major problem. Dioxins are formed as important toxic side products in the production of PCBs, chlorophenols, chlorophenoxy acid herbicides,
and other chlorinated organic chemicals. This caused very high
exposures to workers in poorly controlled hygienic conditions. Many
workers had chloracne. In a NIOSH
study in the U.S., the average concentration of TCDD in exposed persons
was 233 ng/kg (in serum lipid) while it was 7 ng/kg in unexposed
workers, even though the exposure had been 15–37 years earlier.
This indicates a huge previous exposure. In fact the exact
back-calculation is debated, and the concentrations may have been even
several times higher than originally estimated.
Handling and spraying of chlorophenoxy acid herbicides may also cause quite high exposures, as clearly demonstrated by the users of Agent Orange in the Malayan Emergency and in the Vietnam War.
The highest concentrations were detected in nonflying enlisted
personnel (e.g. filling the tanks of planes), although the variation was
huge, 0 to 618 ng/kg TCDD (mean 23.6 ng/kg). Other occupational exposures (working at paper and pulp mills, steel mills and incinerators) have been remarkably lower.
Accidental exposures have been huge in some cases. The highest concentrations in people after the Seveso accident were 56,000 ng/kg, and the highest exposure ever recorded was found in Austria in 1998, 144,000 ng/kg. This is equivalent to a dose of 20 to 30 μg/kg TCDD, a dose that would be lethal to guinea pigs and some rat strains.
Exposure from contaminated soil is possible when dioxins are
blown up in dust, or children eat dirt. Inhalation was clearly
demonstrated in Missouri in the 1970s, when waste oils were used as dust
suppressant in horse arenas. Many horses and other animals were killed
due to poisoning.
Dioxins are neither volatile nor water-soluble, and therefore exposure
of human beings depends on direct eating of soil or production of dust
which carries the chemical. Contamination of ground water or breathing
vapour of the chemical are not likely to cause a significant exposure.
Currently, in the US, there are 126 Superfund sites with a completed exposure pathway contaminated with dioxins.
Further, PCBs are known to pass through treatment plants and accumulate in sludge which is used on farm fields in certain countries. In 2011 in South Carolina, SCDHEC enacted emergency sludge regulations after PCBs were found to have been discharged to a waste treatment plant.
PCBs are also known to flush from industry and land (aka sludge fields) to contaminate fish,
as they have up and down the Catawba River in North and South Carolina.
State authorities have posted fish consumption advisories due to
accumulation of PCBs in fish tissue.
TEF values
All
dioxin-like compounds share a common mechanism of action via the aryl
hydrocarbon receptor (AHR), but their potencies are very different. This
means that similar effects are caused by all of them, but much larger
doses of some of them are needed than of TCDD. Binding to the AHR as
well as persistence in the environment and in the organism depends on
the presence of so-called "lateral chlorines", in case of dioxins and
furans, chlorine substitutes in positions 2,3,7, and 8.
Each additional non-lateral chlorine decreases the potency, but
qualitatively the effects remain similar. Therefore, a simple sum of
different dioxin congeners is not a meaningful measure of toxicity. To
compare the toxicities of various congeners and to render it possible to
make a toxicologically meaningful sum of a mixture, a toxicity
equivalency (TEQ) concept was created.
Each congener has been given a toxicity equivalence factor (TEF). This indicates its relative toxicity as compared with TCDD. Most TEFs have been extracted from in vivo toxicity data on animals, but if these are missing (e.g. in case of some PCBs), less reliable in vitro data have been used.
After multiplying the actual amount or concentration of a congener by
its TEF, the product is the virtual amount or concentration of TCDD
having effects of the same magnitude as the compound in question. This
multiplication is done for all compounds in a mixture, and these
"equivalents of TCDD" can then simply be added, resulting in TEQ, the
amount or concentration of TCDD toxicologically equivalent to the
mixture.
The TEQ conversion makes it possible to use all studies on the
best studied TCDD to assess the toxicity of a mixture. This resembles
the common measure of all alcoholic drinks: beer, wine and whiskey can
be added together as absolute alcohol, and this sum gives the
toxicologically meaningful measure of the total impact.
The TEQ only applies to dioxin-like effects mediated by the AHR.
Some toxic effects (especially of PCBs) may be independent of the AHR,
and those are not taken into account by using TEQs.
TEFs are also approximations with certain amount of scientific
judgement rather than scientific facts. Therefore, they may be
re-evaluated from time to time. There have been several TEF versions
since the 1980s. The most recent re-assessment was by an expert group of
the World Health organization in 2005.
