toxicity
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...
of
dioxins
Dioxin may refer to:
* 1,2-Dioxin or 1,4-Dioxin, two unsaturated heterocyclic 6-membered rings where two carbon atoms have been replaced by oxygen atoms, giving the molecular formula C4H4O2
*Dibenzo-1,4-dioxin, the parent compound also known as ...
,
furans
Furan is a heterocyclic organic compound, consisting of a five-membered aromatic ring with four carbon atoms and one oxygen atom. Chemical compounds containing such rings are also referred to as furans.
Furan is a colorless, flammable, highly ...
and
PCBs
Polychlorinated biphenyls (PCBs) are highly carcinogenic chemical compounds, formerly used in industrial and consumer products, whose production was banned in the United States by the Toxic Substances Control Act in 1979 and internationally by t ...
in terms of the most toxic form of dioxin, 2,3,7,8-TCDD.Van den Berg M, Birnbaum LS, Denison M, De Vito M, Farland W, Feeley F, Fiedler H, Hakansson H, Hanberg A, Haws L, Rose M, Safe S, Schrenk D, Tohyama C, Tritscher A, Tuomisto J, Tysklind M, Walker N, Peterson RE. 2006. The 2005 World Health Organization reevaluation of human and mammalian toxic equivalency factors for dioxins and dioxin-like compounds, Toxicol. Sci. 93:223–241. The toxicity of the individual congeners may vary by
orders of magnitude
An order of magnitude is an approximation of the logarithm of a value relative to some contextually understood reference value, usually 10, interpreted as the base of the logarithm and the representative of values of magnitude one. Logarithmic dis ...
.
With the TEFs, the toxicity of a mixture of dioxins and dioxin-like compounds can be expressed in a single number - the toxic equivalency (TEQ). It is a single figure resulting from the product of the concentration and individual TEF values of each congener.
The TEF/TEQ concept has been developed to facilitate
risk assessment
Broadly speaking, a risk assessment is the combined effort of:
# identifying and analyzing potential (future) events that may negatively impact individuals, assets, and/or the environment (i.e. hazard analysis); and
# making judgments "on the to ...
and regulatory control. While the initial and current set of TEFs only apply to dioxins and dioxin-like chemicals (DLCs), the concept can theoretically be applied to any group of chemicals satisfying the extensive similarity criteria used with dioxins, primarily that the main mechanism of action is shared across the group. Thus far, only the DLCs have had such a high degree of evidence of toxicological similarity.
There have been several systems over the years in operation, such as the International Toxic Equivalents for dioxins and furans only, represented as I-TEQDF, as well as several country-specific TEFs. The present
World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
scheme, represented as WHO-TEQDFP, which includes
PCBs
Polychlorinated biphenyls (PCBs) are highly carcinogenic chemical compounds, formerly used in industrial and consumer products, whose production was banned in the United States by the Toxic Substances Control Act in 1979 and internationally by t ...
is now universally accepted.
Chemical mixtures and additivity
Humans and wildlife are rarely exposed to solitary contaminants, but rather to complex mixtures of potentially harmful compounds. Dioxins and DLCs are no exception.Van den Berg M, Birnbaum L, Bosveld ATC, Brunstrom B, Cook P, Feeley M, Giesy JP, Hanberg A, Hasegawa R, Kennedy SW, Kubiak T, Larsen JC, van Leeuwen FXR, Djien Liem AK, Nolt C, Peterson RE, Poellinger L, Safe S, Schrenk D, Tillitt D, Tysklind M, Younes M, Waern F, Zacharewski T. 1998. Toxic Equivalency Factors (TEFs) for PCBs, PCDDs, PCDFs for Humans and Wildlife. Environ. Health Perspect. 106:775-792. This is important to consider when assessing toxicity because the effects of chemicals in a mixture are often different from when acting alone. These differences can take place on the chemical level, where the properties of the compounds themselves change due to the interaction, creating a new dose at the target tissue and a quantitatively different effect. They may also act together (simple similar action) or independently on the organism at the
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
during uptake, when transported throughout the body, or during
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
, to produce a joint effect. Joint effects are described as being additive (using dose, response/risk, or measured effect),
synergistic
Synergy is an interaction or cooperation giving rise to a whole that is greater than the simple sum of its parts. The term ''synergy'' comes from the Attic Greek word συνεργία ' from ', , meaning "working together".
History
In Christi ...
, or antagonistic. A dose-additive response occurs when the mixture effect is determined by the sum of the component chemical doses, each weighted by its relative toxic potency. A risk-additive response occurs when the mixture response is the sum of component risks, based on the probability law of independent events. An effect-additive mixture response occurs when the combined effect of exposure a chemical mixture is ''equal to'' the sums of the separate component chemical effects, e.g., incremental changes in relative liver weight. Synergism occurs when the combined effect of chemicals together is ''greater than'' the additivity prediction based on their separate effects. Antagonism describes where the combined effect is ''less than'' the additive prediction. Clearly it is important to identify which kind of additivity is being used. These effects reflect the underlying
modes of action A mode of action (MoA) describes a functional or anatomical change, resulting from the exposure of a living organism to a substance. In comparison, a mechanism of action (MOA) describes such changes at the molecular level.
A mode of action is impor ...
and mechanisms of toxicity of the chemicals.U.S. EPA. 2000. Supplementary Guidance for Conducting Health Risk Assessment of Chemical Mixtures. EPA/630/R-00/002. Washington, DC:Risk Assessment Forum.
Additivity is an important concept here because the TEF method operates under the assumption that the assessed contaminants are dose-additive in mixtures. Because dioxins and DLCs act similarly at the AhR, their individual quantities in a mixture can be added together as proportional values, i.e. TEQs, to assess the total potency. This notion is fairly well supported by research.Environmental Protection Agency. 2010. Recommended Toxicity Equivalence Factors (TEFs) for Human Health Risk Assessments of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and Dioxin-Like Compounds. Some interactions have been observed and some uncertainties remain, including application to other than oral intake.
TEF
Exposure to environmental media containing 2,3,7,8-TCDD and other
dioxins and dioxin-like compounds
Dioxins and dioxin-like compounds (DLCs) are a group of chemical compounds that are persistent organic pollutants (POPs) in the environment. They are mostly by-products of burning or various industrial processes - or, in case of dioxin-like PCBs an ...
can be harmful to humans as well as to wildlife. These chemicals are resistant to
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
and
biomagnify
Biomagnification, also known as bioamplification or biological magnification, is any concentration of a toxin, such as pesticides, in the tissues of tolerant organisms at successively higher levels in a food chain. This increase can occur as a ...
up the food chain. Toxic and biological effects of these compounds are mediated through the aryl hydrocarbon receptor (AhR). Oftentimes results of human activity leads to instances of these chemicals as mixtures of DLCs in the environment. The TEF approach has also been used to assess the toxicity of other chemicals including PAHs and xenoestrogens.Safe S. 1998. Hazard and Risk Assessment of Chemical Mixtures Using the Toxic Equivalency Factor Approach. Environmental Health Perspectives 106:1051-1058
The TEF approach uses an underlying assumption of additivity associated with these chemicals that takes into account chemical structure and behavior. For each chemical the model uses comparative measures from individual toxicity assays, known as relative effect potency (REP), to assign a single scaling factor known as the TEF.
TCDD
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the reference chemical to which the toxicity of other dioxins and DLCs are compared. TCDD is the most toxic DLC known. Other dioxins and DLCs are assigned a scaling factor, or TEF, in comparison to TCDD. TCDD has a TEF of 1.0. Sometimes PCB126 is also used as a reference chemical, with a TEF of 0.1.
Determination of TEF
TEFs are determined using a database of REPs that meet WHO established criteria, using different biological models or endpoints and are considered estimates with an order of magnitude of uncertainty. The characteristics necessary for inclusion of a compound in the WHO‘s TEF approach include:
*Structural similarity to polychlorinated dibenzo-p-dioxins or polychlorinated dibenzofurans
*Capacity to bind to the aryl hydrocarbon receptor (AhR)
*Capacity to elicit AhR-mediated biochemical and toxic responses
*Persistence and accumulation in the food chain
All viable REPs for a chemical are compiled into a distribution, and the TEF is selected based on half order of magnitude increments on a logarithmic scale. The TEF is typically selected from the 75th percentile of the REP distribution in order to be protective of health.
''In vivo'' and ''in vitro'' studies
REP distributions are not weighted to give more importance to certain types of studies. Current focus of REPs is on ''
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
'' studies rather than ''
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
''. This is because all types of ''in vivo'' studies (
acute
Acute may refer to:
Science and technology
* Acute angle
** Acute triangle
** Acute, a leaf shape in the glossary of leaf morphology
* Acute (medicine), a disease that it is of short duration and of recent onset.
** Acute toxicity, the adverse eff ...
, subchronic, etc.) and different endpoints have been combined, and associated REP distributions are shown as a single box plot.
TEQ
Toxic Equivalents (TEQs) report the toxicity-weighted masses of mixtures of PCDDs, PCDFs, and PCBs. The reported value provides toxicity information about the mixture of chemicals and is more meaningful to toxicologists than reporting the total number of grams. To obtain TEQs the mass of each chemical in a mixture is multiplied by its TEF and is then summed with all other chemicals to report the total toxicity-weighted mass. TEQs are then used for risk characterization and management purposes, such as prioritizing areas of cleanup.
Calculation
The toxic equivalency of a mixture is defined by the sum of the concentrations of individual compounds (Ci) multiplied by their relative toxicity (TEF):
Risk assessment
Broadly speaking, a risk assessment is the combined effort of:
# identifying and analyzing potential (future) events that may negatively impact individuals, assets, and/or the environment (i.e. hazard analysis); and
# making judgments "on the to ...
is the process by which one estimates the probability of some adverse effect, such as that of a contaminant in the environment. Environmental risk assessments are conducted to help protect human health and the environment and are often used to assist in meeting regulations such as those stipulated by
CERCLA
Superfund is a United States federal environmental remediation program established by the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA). The program is administered by the Environmental Protection Agency ...
in the United States. Risk assessments may take place retroactively, i.e., when assessing the contamination hazard at a superfund site, or predictively, such as when planning waste discharges.
The complex nature of chemicals mixtures in the environment presents a challenge to risk assessment.Safe S. 1998. Hazard and Risk Assessment of Chemical Mixtures Using the Toxic Equivalency Factor Approach. Environmental Health Perspectives 106:1051-1058 The TEF approach was developed to help assess the toxicity of DLCs and other environmental contaminants with additive effects and is currently endorsed by the World Health Organization
Human health
Human exposure to dioxins and DLCs is a cause for public and regulatory concern. Health concerns include endocrine, developmental, immune and carcinogenic effects.World Health Organization (WHO). 1998. Assessment of the health risk of dioxins: re-evaluation of the Tolerable Daily Intake (TDI). WHO European Centra for Environment and Health International Programme on Chemical Safety. The route of exposure is primarily through the ingestion of animal products such as meat, dairy, fish, and human breast milk. However, humans are also exposed to high levels of “natural dioxins” in cooked foods and vegetables. The human diet accounts for over 95% of the total uptake of TEQ.
Risks in humans are typically calculated from known ingestion of contaminants or from blood or adipose tissue samples. However, human intake data is limited, and calculations from blood and tissue are not well supported. This presents a limitation to the TEF application in risk assessment to humans.van Ede KI, Anderson PL, Gaisch KPJ, van den Berg M, van Duursen MBM. 2013. Comparison of Intake and Systemic Relative Effect Potencies of Dioxin-like Compounds in Female Mice after a Single Oral Dose. Environmental Health Perspectives, online.
Fish and wildlife
DLC exposure to wildlife results from various sources including the atmospheric deposition of emissions (e.g. waste incineration) over terrestrial and aquatic habitats and contamination from waste effluents. Contaminants then bioaccumulate up the food chain. The WHO has derived TEFs for fish, bird, and mammal species, however differences among taxa for some compounds are orders of magnitude apart. Compared to mammals, fish are less responsive to mono-ortho PCBs.
Limitations
The TEF approach DLC risk assessment operates under certain assumptions which attach varying degrees of uncertainty. These assumptions include:
*Individual compounds all act through the same biologic pathway
*Individual effects are dose-additive
*Dose-response curves are similarly shaped
*Individual compounds are similarly distributed throughout the body
TEFs are assumed to be equivalent for all effects, all exposure scenarios and all species, although this may not be the reality. The TEF method only accounts for toxicity effects related to the AhR mechanism - however, some DLC toxicity may be mediated through other processes. Dose-additivity may not be applicable to all DLCs and exposure scenarios, particularly those involving low doses. Interactions with other chemicals that may induce antagonistic effects are not considered and those may be species-specific. In terms of human health risk assessments, estimates of relative potency from animal studies are assumed to be predictive of toxicity in humans, although there are species-specific differences in the AhR. Nevertheless, ''In vivo'' mixture studies have shown that WHO 1998 TEF values predicted mixture toxicity within a factor of two or less
A probabilistic approach may provide an advantage in the determination of TEF because it will better describe the level of uncertainty present in a TEF value
The use of TEF values to assess abiotic matrices such as soil, sediment, and water is problematic because TEF values are primarily calculated from oral intake studies.
History and development
Dating back to the 1980s there is a long history of developing TEFs and how to use them. New research being conducted influences guiding criteria for assigning TEFs as the science progresses. The World Health Organization has held expert panels to reach a global consensus on how to assign TEFs in conjunction with new data. Each individual country recommends their own TEF values, typically endorsing the WHO global consensus TEFs.
Other compounds for potential inclusion
Based on mechanistic considerations, PCB 37, PBDDs, PBDFs, PXCDDs, PXCDFs, PCNs, PBNs and PBBs can be included in the TEF concept. However, most of these compounds lack human exposure data. Thus, TEF values for these compounds are in the process of review
See also
*
Dioxins and dioxin-like compounds
Dioxins and dioxin-like compounds (DLCs) are a group of chemical compounds that are persistent organic pollutants (POPs) in the environment. They are mostly by-products of burning or various industrial processes - or, in case of dioxin-like PCBs an ...