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The general public is principally exposed to PCDDs by the ingestion of contaminated food and, to a lesser extent, by inhaling atmospheric releases. Animals intended for human consumption graze on grass and leafy vegetation and ingest small amounts of soil that contain PCDDs deposited from atmospheric releases. Food-producing livestock may also contact PCDDs from pesticide applications, wood preservatives, and the application of sewage sludge to fields. PCDDs are accumulated in the tissues and milk of livestock providing an entry into the food chain. Some plants such as pumpkins and courgette (zucchini) can also take up and distribute PCDDs, and these compounds may also be taken up into the outer layers of potatoes and carrots. Industrial accidents have resulted in the environmental release of PCDDs and the exposure of the general public. A particularly well-known and heavily researched example of such an accident took place in 1976 at Seveso, Italy, when a valve malfunction in a chlorinated herbicide manufacturing plant released PCDDs to the environment, exposing wildlife and the general public. Electrical fires in transformers and circuit breakers have involved the accidental incineration of polychlorinated biphenyl (PCB)-containing oils, and have also released PCDDs to the atmosphere. The use of PCDD-contaminated oil as a dust control measure in Times Beach, Missouri resulted in the permanent relocation of the population to prevent further exposure, the demolition of dwellings, and the removal of contaminated soil. Occupational exposure to incidental PCDDs may occur during the manufacture of chlorinated herbicides, wood preservatives, and pesticides, during paper and pulp bleaching, and in emergency response to fires involving PCB-containing dielectric fluids. Industrial exposure to PCDDs is generally by skin contact or inhalation.
PCDDs present in animal fats and vegetable oils are efficiently absorbed from the gastrointestinal tract and readily pass into the lymphatic system and blood in chylomicrons, microscopic droplets of newly absorbed fat bounded by a lipoprotein membrane. There is rapid clearance of chylomicrons from the blood, and ingested PCDDs appear in the liver and fatty tissues. A small proportion of PCDDs remain in the blood, bound to serum lipoproteins. Animal studies show that PCDDs readily pass through the placenta to the developing fetus.
The principal route of elimination of PCDDs in humans is fecal excretion, although there is some evidence that metabolic elimination also takes place. Half an absorbed dose of PCDDs is eliminated within 28 days in both rats and mice, but the data suggest that the half-life of PCDDs in humans is considerably longer. Young adults clear PCDDs more rapidly than the elderly, and the half-lives of these compounds range from 5 years in young adults to 11 years in elderly men.
Not all of the compounds that comprise the PCDDs are equally toxic. The most toxic compound is 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD). TCDD is given a value of 1 by the World Health Organization (WHO) on their Toxic Equivalency Factor (TEF) scale. Other PCDDs showing 2,3,7,8- substitution are ranked in relationship to TCDD, from the most to least toxic. Although 1,2,3,7,8-pentachlorodibenzo-p-dioxin is also rated 1 by WHO, the hexa-, hepta-, and octa-chlorinated compounds that show the 2,3,7,8- pattern of substitution are ranked 0.1, 0.01, and 0.0001, respectively. However, PCDDs are most usually present in the environment as mixtures rather than as a single compound. In a mixture, each PCDD congener is assumed to have an additive effect, and exerts its toxic action independently of the other components in the mixture.
Animal studies indicate that the PCDDs exert their toxic effects through a common mechanism, binding to the intracellular aryl hydrocarbon (Ah) receptor. Persistent, undesirable changes in metabolism are seen in response to the adherence of PCDDs to the Ah receptor. Changes in thyroid metabolism may ultimately result in chronic stimulation of the thyroid and potentially to thyroid cancer. Alterations in estrogen metabolism may result in cancer of the liver by disrupting the plasma membrane system responsible for controlling cellular proliferation.
Results of animal studies of the acute toxicity of TCDD vary widely according to the species under test. An oral median lethal dose (LD50) (the single dose that kills 50 percent of the test animals in a specified time) of 0.6 micrograms per kilogram body weight (µg/kg) has been observed for the guinea pig as compared to an LD50 of >5000 µg/kg for the Syrian golden hamster. Short-term studies of the effects of TCDD using rats and guinea pigs yield similar results, including changes in the liver metabolism (enzyme induction), significant decrease in the levels of circulating thyroid hormones, and changes in organ and body weights. Mice exposed to short-term PCDDs showed induction of liver enzymes and the accumulation of compounds in the liver that can cause porphyria, a disease characterized by disturbances in the nervous system and skin.. TCDD included in the diet of female rhesus monkeys for 9 months resulted in the development of dermatological effects after 3 months, and changes in hemoglobin levels and erythrocyte volumes.
Many long-term studies of the toxicity and carcinogenicity of the PCDDs have been performed on mice, rats, and non-human primates such as rhesus monkeys. Mouse studies report the development of hepatocellular adenoma or carcinoma, increases in the incidence of thyroid follicular adenoma, and histiocytic lymphoma. An increased incidence of cancers arising in the tissues of the thyroid gland and liver is also observed in rats. In addition, kidney, skin and lung cancers, cancers arising in the tissues lining the lung and palate, and leukemia have also been reported in this species. Groups of female rhesus monkeys were given TCDD in their diet, providing a dose of 0,15 and 0.67 ng/kg-day for 3.5-4 years. Monkeys in the higher dose group showed marginal signs of toxicity.
TCDD gives both negative and positive results in short-term genotoxicity assays, in vitro and in vivo. Neither TCDD nor octachlorinated dibenzo-p-dioxin induce mutations in Salmonella typhimurium, with or without an exogenous metabolic activation system added to the test system. Human white blood cells treated with TCDD showed some evidence of chromosome alterations. TCDD does not bind to mouse liver DNA, but does induce DNA single-strand breaks in isolated cells derived from rats.
Animal studies demonstrate PCDDs to be reproductive toxins, affecting fertility and several aspects of fetal development. Multigenerational dietary studies on the reproductive toxicity of TCDD on the rat showed that fertility, litter size, and neonatal survival were greatly decreased at the highest dose level. These effects were also seen at the intermediate dose level in ensuing generations. Slight effects on renal morphology and pup survival were observed at the lowest dose. Reproductive failure was seen in rhesus monkeys fed diets containing TCDD at 50 or 500 pg/g for 7 months. Two monkeys out of 8 in the 50 pg/g group and 1 of 8 in the 500 pg/g group carried their offspring to term. At doses below those associated with maternal toxicity, PCDDs can induce effects that include fetal mortality, structural malformations, and changes in post natal function in a variety of species. Cleft palate and kidney abnormalities are produced by TCDD in mice at doses that do not cause maternal toxicity. Cleft palate is not usually seen in response to TCDD in species other than mice. Gastrointestinal hemorrhage, swelling, and renal malformations are more usual in rats and Syrian golden hamsters. Detrimental changes to the male reproductive system have been noted in Long-Evans rats, whose dams were given a single dose of TCDD on day 15 of gestation. Genitourinary malformations were also noted in the female offspring of treated rats.
Epidemiological studies provide 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 (contaminated with PCDDs) as a defoliant in the Vietnam war. The general population exposed to PCDDs at Seveso has been extensively researched. A review performed by the World Health Organization (WHO) on the risks of PDCCs considered industrial epidemiological studies where the exposure to the compounds was adequately assessed. WHO concluded that low excess risks of neoplasms were found by the studies, and that these excess risks were statistically highly significant, effectively eliminating the possibility that the effects were due to chance. The most heavily exposed workers were at increased risk, and risks increased with time since the first exposure. Some studies considered by WHO reported increased risks for specific cancers, such as cancers of the bone marrow, lymphatic system, lung, liver, testes, lining of the uterus, breast and soft tissues, but there were no consistent results among the studies. WHO concluded that no one cancer appeared to predominate.
Many adverse, non-cancer, human health effects have been reported as due to PDCC exposure, including skin lesions such as chloracne, malfunction of the sebaceous glands of the eyelids, coughing and respiratory irritation, peripheral neuropathy, and developmental defects. Animal studies suggest that these effects are plausible. In addition to investigating cancer effects, the WHO considered a wider range of epidemiological studies to evaluate the non-cancer effects of TCDD. These studies provide strong evidence of an association between TCDD exposure and chloracne, and also temporary increases in liver enzymes. Positive associations were demonstrated between TCDD exposure and cardiovascular disease and alterations in lipid concentrations. Increased risk of diabetes was identified in the population of Seveso and US service personnel who sprayed herbicides in Vietnam, although overall results are not entirely consistent. Inconsistent results from TCDD exposure were seen in compound-related effects on reproductive hormones, but an altered sex ratio was seen in the infants of heavily exposed couples in Seveso. Small and inconsistent effects of TCDD were seen in the thyroid hormones. Inconsistent neurological effects (polyneuropathy, that is the malfunction of many peripheral nerves over the body, and abnormal co-ordination) were noted as a result of TCDD exposure at Seveso and US army herbicides sprayers in Vietnam. Although respiratory irritation, reduced forced expiratory volume, and forced vital capacity were noted in some studies, the evidence was inconsistent. Inconsistent immunological effects were reported, and no major bladder or renal effects were observed.
The National Toxicology Program's Report on Carcinogens (Eleventh Edition) lists TCDD as "known to be a human carcinogen". The US Environmental Protection Agency 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".
NTP (National Toxicology Program). (2006) Report on Carcinogens, eleventh edition.
U.S. Department of Human Services, Public Health Service, National Toxicology Program.
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
US Environmental Protection Agency Integrated Risk Information System 1991
Safety Evaluation of Certain Food Additives and Contaminants: Polychlorinated Dibenzodioxins, Polychlorinated Dibenzofurans, and Coplanar Polychlorinated Biphenyls
R. Canady, K. Crump, M. Feeley, J. Freijer, M. Kogevinas, R. Malisch, P. Verger, J. Wilson and M. Zeilmake.
World Health Organization (WHO), Food Additives Series, Vol 48, 2002.
Toxicological Profile for Chlorinated Dibenzo-p-dioxins (CDDs)
Agency for Toxic Substances and Disease Registry (ATSDR) (1998)
Bioavailability of Dioxins and Dioxin-Like Compounds in Soil
U.S. EPA, Office of Superfund Remediation and Technology Innovation, 83 pp, December 2010.
Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Final Report
National Research Council, National Academies Press, 59 pp, 2003.
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.
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.
- Soil Guideline Values for Dioxins, Furans and Dioxin-Like PCBs in Soil (2009)
- Supplementary Information for the Derivation of SGVs for Dioxins, Furans and Dioxin-Like PCBs (2009)
- Contaminants in Soil: Updated Collation of Toxicological Data and Intake Values for Humans: Dioxins, Furans and Dioxin-Like PCBs (2009)
- Dioxins Site-Specific Worksheets
- CLEA Software and Dioxins Workbook
U.S. EPA, National Center for Environmental Assessment, 2007
Dioxin and Dioxin-Like Compounds in Soil, Part 1: ATSDR Interim Policy Guideline
Christopher De Rosa, et al.
Toxicology and Industrial Health, Vol 13 No 6, p 759-768, 1997.
Center for Disease Control, Agency for Toxic Substances and Disease Registry.
Dioxin: Seveso Disaster Testament to Effects of Dioxin
Corliss, M. (1999).
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.
An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Volume I: 1997 Follow-up Examination Results
J.E. Michalek, H.E. Marden Jr., J.N. Robinson, V.V. Elequin, J.C. Miner.
ADA408237, 1,744 pp, 2000.
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
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
The profile provides environmental health scientists with approaches for the incorporation of the whole mixture data or the concerns for additivity and interactions into an assessment of the potential health hazard of this mixture of CDDs, hexachlorobenzene, p,p'-DDE, methylmercury, and PCBs. The approaches can then be used with specific exposure data from hazardous waste sites or other exposure scenarios.
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
The primary purpose of this Interaction Profile for CDDs, hexachlorobenzene, p,p'-DDE, methylmercury, and PCBs is to evaluate data on the toxicology of the mixture as a whole and the joint toxic action of the chemicals in the mixture in order to recommend approaches for assessing the potential health hazard of this mixture. This Profile also serves as a support document for ATSDR's Great Lakes Research Program. The five chemicals were selected because (1) each occurs with high frequency in Great Lakes water, sediment, and biota; (2) each has been associated with a wide array of overlapping toxic effects leading to concerns that they may jointly act on several similar targets of toxicity; (3) neurological development associated with pre- or post-natal oral exposure is a critical toxicity target for each; and (4) studies are reporting adverse developmental effects in children.
Methodology for Assessing Health Risks Associated With Multiple Pathways of Exposure to Combustor Emissions
EPA 600-R-98-137, 613 pp, 1998.
Contact: Eletha G. Brady-Roberts,, firstname.lastname@example.org
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
A Toxicity Equivalency Factor Procedure For Estimating 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Equivalents in Mixtures of Polychlorinated Dibenzo-p-Dioxins and Polychlorinated Dibenzofurans
John Brantner and Richard Becker.
California Department of Toxic Substances Control, 1992.
National Library of Medicine Specialized Information Services.
This site contains a cluster of databases on toxicology, hazardous chemicals, and related areas, including the Hazardous Substances Data Bank (HSDB), Integrated Risk Information System (IRIS), and Toxics Release Inventory (TRI). The site supports simultaneous searching in multiple databases.
Very few studies address the issue of PCDD toxicity in plants. However, it would appear 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 10-1,000 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.
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
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
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, email@example.com
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
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.
Contact: Christopher Cubbison, firstname.lastname@example.org
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.
Contact: Joan U. Clarke, Joan.Clarke@erdc.usace.army.mil
Compilation of EU Dioxin Exposure and Health Data, Task 7: Ecotoxicology
European Commission DG Environment, UK Department of the Environment, Transport and the Regions, 41 pp, 1999.
Framework for Application of the Toxicity Equivalence Methodology for Polychlorinated Dioxins, Furans and Biphenyls in Ecological Risk Assessment (External Review Draft)
U.S. EPA, Risk Assessment Forum.
EPA 630-P-03-002A, 94 pp, 2003.
Contact: William P. Wood, email@example.com
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, firstname.lastname@example.org