Dioxins

Toxicology

People are primarily exposed to PCDDs by ingesting contaminated food — particularly meat, dairy, and fish — and to a lesser extent by inhaling atmospheric releases from combustion sources. Meat and dairy can contain PCDDs because animals ingest small amounts of soil when grazing on grass and leafy vegetation. Similarly, fish may incidentally ingest PCDDs found in sediment. PCDDs accumulate in the tissues and milk of livestock and aquatic organisms providing an entry into the food chain. People also ingest typically smaller amounts of PCDDs when consuming root vegetables, like potatoes and carrots, that may take up PCDDs from contaminated soil.

Industrial accidents have resulted in environmental release and public exposure of PCDDs. One well-known and heavily researched example of such an accident took place in 1976 in Seveso, Italy, when a valve malfunction in a chlorinated herbicide manufacturing plant released CDDs to the environment, exposing wildlife and the public.

Occupational exposure to PCDDs is generally through skin contact or inhalation. Incidental exposure to PCDDs may occur during the manufacture or application of chlorinated herbicides, wood preservatives, and pesticides, during paper and pulp bleaching, and in emergency response to fires involving PCB-containing dielectric fluids.

Human Health

TCDD is considered the most toxic of the PCDD congeners and dioxin-like compounds, which typically occur as mixtures in environmental media (U.S. EPA, 2013). Based on human and animal studies, the National Toxicology Program's Report on Carcinogens (14th Edition) lists TCDD as a known human carcinogen. EPA also classifies hexachlorodibenzo-p-dioxin (HxCDD), a mixture of 1,2,3,6,7,8-Hx and 1,2,3,6,7,9-HxCDD, as "B2 – probable human carcinogen" (U.S. EPA, 1991). In 2012, EPA finalized an Integrated Risk Information System (IRIS) assessment, which established an oral non-cancer toxicity value, or reference dose (RfD), for oral exposure (ingestion) to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (U.S. EPA, 2012). An RfD is the estimate (with uncertainty that may span an order of magnitude) of daily oral exposure that is likely to be without an appreciable risk of deleterious effects during a person's lifetime (including sensitive subgroups); it is used to develop site-specific risk-based cleanup levels at Superfund sites. The basis for the TCDD RfD of 7x10^-10 mg/kg/day was identified as decreased sperm count and motility in men exposed to TCDD as boys and increased thyroid-stimulating hormones (TSH) in neonates.

In conducting risk assessments, the toxicity of other dioxins and dioxin-like compounds is addressed by considering their toxicity relative to TCDD (U.S. EPA, 2013). The comparison is done using toxic equivalency factors (TEFs) developed by the World Health Organization. TCDD is assigned a TEF of 1. A congener considered one-tenth as toxic as TCDD is given a TEF of 0.1. In mixtures, the toxicity of the various PCDDs and dioxin-like compounds are assumed to have an additive effect.

The TEFs are most appropriate for dioxin exposures via the ingestion pathway. The ingestion pathway for TCDD drives risk CERCLA and RCRA assessments. The TEFs can be used for evaluating the risk posed by the ingestion of soil, sediments, water, and fish contaminated with TCDD and DLCs.

Animal studies indicate that the PCDDs exert their toxic effects through a common mechanism, binding to the intracellular aryl hydrocarbon (Ah) receptor. The carcinogenic effect of dioxins is likely the result of tumor-promoting activity produced by activation of the AhR. For the purpose of risk assessment extrapolation from effects in the observable high dose range to background dietary exposure is necessary (U.S. Department of Human Services, 2016). Persistent, undesirable changes in metabolism are seen in response to the adherence of PCDDs to the Ah receptor. The acute toxicity of TCDD is considerable but results of animal studies show the acute toxicity varies widely according to the species under test (Hites, R.A., 2011; Canady, et al.; 2002; NIOSH, 1984). Other dioxin and furan congeners are also toxic, and many of these compounds have both acute and chronic effects (Hites, R.A., 2011).

Epidemiological studies have provided information on the cancer and non-cancer effects of the PCDDs on exposed workers in the chemical manufacturing industries and military personnel who used Agent Orange, which contained traces of PCDDs, as a defoliant in the Vietnam war (U.S. DHS, 2016; Canady, et al., 2002).

Reported adverse, non-cancer, human health effects due to PDCC exposure, include skin lesions such as chloracne, malfunction of the sebaceous glands of the eyelids, coughing and respiratory irritation, peripheral neuropathy, and developmental defects.

References:

Agency for Toxic Substances and Disease Registry (ATSDR),1998. Toxicological Profile for Chlorinated Dibenzo-p-dioxins (CDDs).

Canady, R., et al., 2002. Safety Evaluation of Certain Food Additives and Contaminants: Polychlorinated Dibenzodioxins, Polychlorinated Dibenzofurans, and Coplanar Polychlorinated Biphenyls. World Health Organization (WHO), Food Additives Series, Vol 48.

Hites, R.A., 2011. Dioxins: An Overview and History. Environmental Science & Technology Feature. 45:16-20.

NIOSH (National Institute of Occupational Safety and Health), 1984. 2,3,7,8 – Tetrachlorodibenzo-p-dioxin (TCDD, "dioxin"). DHHS (NIOSH) Publication Number 84-104.

Pohjanvirta R. et al., 1993. Comparative Acute Lethality of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-Pentachlorodibenzo-p-dioxin and 1,2,3,4,7,8-Hexachlorodibenzo-p-dioxin in the Most TCDD-Susceptible and the Most TCDD-Resistant Rat Strain. Pharmacological Toxicology. Jul;73(1):52-6.

U.S. DHS (Department of Human Services), 2016. National Toxicology Program Report on Carcinogens, Fourteenth edition. November 3, 2016. Public Health Service, National Toxicology Program.

U.S. EPA, 2013. Use of Dioxin TEFs in Calculating Dioxin TEQs at CERCLA and RCRA Sites. May.

U.S. EPA, 2012. IRIS Chemical Assessment Summary: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD); CASRN 174601-6. National Center for Environmental Assessment. Chemical Assessment Summary Integrated Risk Information System. February 17.

U.S EPA, 1991. Hexachlorodibenzo-p-dioxin (HxCDD), mixture of 1,2,3,6,7,8-HxCDD and 1,2,3,7,8,9-HxCDD; CASRN 57653-85-7 and 19408-74-3. Integrated Risk Information System.

Additional Resources

Soil Dioxin Relative Bioavailability Assay Evaluation Framework
U.S. Environmental Protection Agency, OSWER 9200.2-136, 16 pp, 2015

Until standard procedures for estimating the relative bioavailability (RBA) of PCDD/F in soil are established, there is a need for a consistent approach to evaluate the strengths and weaknesses of assays designs proposed or implemented to support risk assessments. This report offers a framework for making such evaluations. Specific design parameters that should be subject to evaluation are identified and relevant scientific literature is cited where more in-depth discussion can be found. Whenever possible, minimal requirements for study designs are proposed.

Use of Dioxin TEFs in Calculating Dioxin TEQs at CERCLA and RCRA Sites
U.S. EPA, Office of Solid Waste and Emergency Response. 8 pp, May 2013

FAQs and corresponding answers are given for the use of dioxin toxicity equivalence factors in calculating dioxin toxicity equivalence (TEQ) concentrations at Superfund and RCRA sites. This text augments EPA's 2010 "Recommended Toxicity Equivalence Factors (TEFs) for Human Health Risk Assessments of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and Dioxin-Like Compounds."

Tri-Service Environmental Risk Assessment Workgroup Questions/Answers on Dioxin
U.S. Army Corps of Engineers, Directorate of Environmental and Munitions Center of Expertise (EM-CX), 7 pp, 2013

Fact sheet responds to basic questions about dioxins, site characterization, risk assessment, and more.

A Review of Human Carcinogens: 2,3,7,8-Tetrachlorodibenzo-para-dioxin, 2,3,4,7,8- Pentachlorodibenzofuran, and 3,3',4,4',5-Pentachlorobiphenyl
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans.
World Health Organization, International Agency for Research on Cancer (IARC) Monographs, Vol 100F, p 339-378, 2012

EPA's Reanalysis of Key Issues Related to Dioxin Toxicity and Response to NAS Comments, Volume I
U.S. EPA, National Center for Environmental Assessment. EPA 600-R-10-038F, 344 pp + appendices, 2012

This document comprises the first of two EPA reports that together respond to the recommendations and comments on TCDD dose- response assessment in the 2006 NAS report, Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment. Volume 1 contains (1) a systematic evaluation of the peer-reviewed epidemiologic studies and rodent bioassays relevant to TCDD dose-response analysis; (2) dose-response analyses using a TCDD physiologically based pharmacokinetic model that simulates TCDD blood concentrations following oral intake; and (3) an oral reference dose for TCDD.

Human Exposure from Dioxins in Soil
A. Demond, A. Franzblau, D. Garabrant, X. Jiang, P. Adriaens, Q. Chen, B. Gillespie, W. Hao, B. et al.
Environmental Science & Technology 46(3):1296-1302(2012)
DOI: 10.1021/es2022363

This document describes EPA's updated approach for evaluating the human health risks from exposures to environmental media containing dioxin and dioxin-like compounds.

Bioavailability of Dioxins and Dioxin-Like Compounds in Soil
U.S. EPA, Office of Superfund Remediation and Technology Innovation, 83 pp, December 2010.

Contaminants in Soil: Updated Collation of Toxicological Data and Intake Values for Humans. Dioxins, Furans and Dioxin-Like PCBs
Department for Environment, Food and Rural Affairs and the Environment Agency (DEFRA). Environment Agency, UK. ISBN: 978-1-84911-108-9, 54 pp, 2009.

Dioxin
U.S. EPA, National Center for Environmental Assessment, 2007

The 2005 World Health Organization Reevaluation of Human and Mammalian Toxic Equivalency Factors for Dioxins and Dioxin-Like Compounds
Toxicological Sciences, Volume 93, Issue 2, October 2006, Pages 223-241,
Martin Van den Berg, et al.

Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Final Report
National Research Council, National Academies Press, 59 pp, 2003.

Contaminated Land Exposure Assessment (CLEA): UK Environment Agency Resources on Dioxins, Furans, and Dioxin-Like PCBs

The Environment Agency's CLEA project develops tools that provide a methodology to help estimate the risks to people from contaminants in soil on a given site over a long duration of exposure. Software and written guidance have been developed to help identify levels of contamination in soil below which the risks are considered minimal.

Dioxin: Seveso Disaster Testament to Effects of Dioxin
Corliss, M. (1999).

Air Force Health Study. Final Report. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 2002 Follow-Up Examination Results (May 2002-March 2005).
J.E. Michalek, et al., 1,995 pp, March 2005.

Exposure Analysis for Dioxins, Dibenzofurans, and CoPlanar Polychlorinated Biphenyls in Sewage Sludge, Technical Background Document (Draft)
U.S. EPA, Office of Water, 200 pp, May 2002

Exposure and Human Health Reassessment of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and Related Compounds National Academy Sciences (NAS) review draft
U.S. EPA. (2003). National Center for Environmental Assessment.

Health Risks for Dioxin and Related Compounds Evaluation of the EPA Reassessment
National Academy of Sciences Public Summary Report in Brief July 2006

Interaction Profile for Persistent Chemicals found in Breast Milk: Chlorinated Dibenzo-p-Dioxins (CDDs); Hexachlorobenzene; p,p'-DDE; Methylmercury; Polychlorinated Biphenyls (PCBs)
Agency for Toxic Substances and Disease Registry, 228 pp, 2004.
Contact: ATSDR, 1-888-422-8737, ATSDRIC@cdc.gov

Interaction Profile for Persistent Chemicals found in Fish: Chlorinated Dibenzo-p-Dioxins (CDDs); Hexachlorobenzene; p,p'-DDE; Methylmercury; Polychlorinated Biphenyls (PCBs)
Agency for Toxic Substances and Disease Registry, 234 pp, 2004.
Contact: ATSDR, 1-888-422-8737, ATSDRIC@cdc.gov

Ecological Impacts

Very few studies address the issue of PCDD toxicity in plants. However, it appears that plants are not particularly sensitive to these chemicals. TCDD had no observable effect on algae or duckweed exposed to the chemical for 33 days. Similarly, there are few toxicity studies available for the effects of PCDDs on freshwater invertebrates or amphibians. Limited information suggests that water snails (Physa sp.), worms (Paranais sp), mosquito larvae (Aedes aegypti), and daphnia (Daphnia magna) are not particularly sensitive to the effects of PCDDs. The little information available for the effects of PCDDs on amphibians indicates that TCDD is not particularly toxic to the bullfrog Rana catesbeiana in either the tadpole stage or as an adult. Tadpoles and adult bullfrogs injected with TCDD at doses of 25,000-1,000,000 or 50,000-500,000 µg/g respectively, did not die within 50 days of dosing (tadpoles), or 35 days (adults). Some effects may have been expected at this fairly large dose. However, the tadpoles successfully completed metamorphosis with no morphological abnormalities and no histopathological lesions of the heart, liver, kidney, lung, or reproductive organs.

Few laboratory studies are available that describe the toxicity of PCDDss to saltwater fish, in contrast to freshwater fish where several studies are available. A dietary study using female brook trout (Salvelinus fontinalis) examined the effects of maternal TCDD ingestion on newly spawned eggs. No effects on fertility, growth, or juvenile sex ratios were reported. A TCDD induced edema was seen in the embryos of all five treatment groups, and an increased incidence of exopthalmia was evident. No adverse histopathological changes were seen in any organs below LC50 egg concentrations. However, cytochrome P4501A1 levels were elevated in the treatment group that achieved an average concentration of 84 pg/g TCDD per egg. Population data suggest that PCDDs were implicated in the decline of fish populations in the Great Lakes. TCDD appears to be strongly associated with the lethal "blue-sac" disease of fry.

Toxicological studies indicate that reptiles are affected by PCDDs. TCDD treatment of American alligator eggs resulted in the hatching of more females than males, at temperatures where a preponderance of male reptiles would have been expected. Male hatchlings showed masses of aberrant cells in the lumens of seminiferous tubules. Abnormalities in snapping turtle hatchlings from locations in the Great Lakes and St. Lawrence River increased significantly with rising PCDD and polychlorinated dibenzofuran (PCDF) concentrations. However, the proportion of unhatched eggs remained constant across all locations, including the reference location. TCDD treatment of isolated hepatocytes from the African brown house snake (Lamprophis fuliginosus) resulted in a dose-dependent increase in enzyme activity comparable to that seen in birds and mammals, and greater than that observed in fish.

Bird species vary widely in their sensitivity to TCDD. The domestic chicken is extremely sensitive to the effects of TCDD and shows mRNA (CYP1A) induction, hepatotoxicity, embryolethality, teratogenicity, and edema in response to TCDD and closely related compounds. The common tern (Sterna hirundo) is 80-250 times less sensitive to TCDD than the chicken, and other bird species are 10- to 1,000-fold less sensitive. These marked contrasts in sensitivity between species appear to be related to species-specific binding affinities of Ah receptors to TCDD. Population data collected from great blue heron colonies in Vancouver, Canada, show an association between TCDD exposure and gross abnormalities in chicks. Abnormalities included edema of the neck, legs, abdomen, and crossed bill. Other studies performed in Washington and Oregon have observed deformed embryos in great blue heron colonies adjacent to paper mills and pulp mills but not at reference sites.

As previously noted, laboratory studies have demonstrated the toxicity of PCDDs to rodents and monkeys, and it can be assumed that wild rodents will be similarly affected. However, there are additional TCDD toxicity data for other terrestrial species such as the mink. A 28-day LD50 of 4.2 µg/kg for TCDD has been calculated for the mink. This implies that this animal is more sensitive to the toxic effects of TCDD than the rat, rabbit, mouse, and hamster, but not as sensitive as the guinea pig.

Adapted from:

Contaminant Exposure and Effects-Terrestrial Vertebrates (CEE-TV) Database
U.S. Geological Survey, Patuxent Wildlife Research Center, Laurel, MD. Version 6, 2006.

Dioxin Hazards to Fish, Wildlife, and Invertebrates: a Synoptic Review
Ronald Eisler.
U.S. Fish and Wildlife Service, Biological Report 85 (1.8), Contaminant Hazard Reviews No. 8, 26 pp, 1986.

Induction of Cytochrome P4501A1 in the African Brown House Snake (Lamprophis fuliginosus) Primary Hepatocytes (Abstract)
Environmental Toxicology and Chemistry 2006 Vol. 25 No. 2 pages 496- 502 2006
Hecker M., Murphy M. B., Giesy J.P. et al

Interim Report on Data and Methods for Assessment of 2,3,7,8-Tetrachlorodibenzo-p-dioxin Risks to Aquatic Life and Associated Wildlife
U.S. EPA, Environmental Research Laboratory, Duluth, MN. EPA 600-R-93-055, 159 pp, 1993.
Contact: William P. Wood, risk.forum@epa.gov

The molecular basis for differential dioxin sensitivity in birds: Role of the aryl hydrocarbon receptor
Published online before print April 10, 2006, 10.1073/pnas.0509950103
Proceedings of the National Academy of Science Vol. 103 No. 16 pages 6252-6257 April 18, 2006 Karchner S.I., Franks D.G., Kennedy S.W. et al

Toxicity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin to Early Life Stage Brook Trout (Salvelinus fontinalis) Following Parental Dietary Exposure
Johnson R.D, Tietge J.E, Jensen K.M., et al Environmental Toxicology and Chemistry Article Volume 17 Issue 12 (December 1998) pp. 2408-2421

Additional Resources

Analyses of Laboratory and Field Studies of Reproductive Toxicity in Birds Exposed to Dioxin-Like Compounds for Use in Ecological Risk Assessment
Glenn Suter II.
EPA 600-R-03-114F, 60 pp, 2003.

Analysis of Uncertainty in Estimating Dioxin Bioaccumulation Potential in Sediment-Exposed Benthos
J.U. Clarke, V.A. McFarland, C.H. Lutz, R.P. Jones, and S.W. Pickard. ERDC TN-DOER-R5, 18 pp, 2004.

Workshop Report on the Application of 2,3,7,8-TCDD Toxicity Equivalence Factors to Fish and Wildlife
U.S. EPA, Risk Assessment Forum. EPA 630-R-01-002, 385 pp, 2001.
Contact: Scott Schwenk, schwenk.scott@epa.gov

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