DIOXINS

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Dioxin
2) Dioxin (agent orange)
3) Agent orange
4) Chlorinated dibenzo-p-dioxins
5) Chlorinated dibenzofurans
6) Chlorinated dioxins
7) D48
8) Dibenzo(b,e)(1,4)dioxin, 2,3,7,8- tetrachloro-
9) Dibenzo-p-dioxin, 2,3,7,8-tetrachloro-
10) Dioksyny
11) Dioxine
12) Dioxin-like compounds
13) PCDD 48
14) TCDBD
15) TCDD
16) 2,3,7,8-TCDD
17) 2,3,7,8-TETRACDD
18) Tetrachlorodibenzodioxin
19) Tetrachlorodibenzo-p-dioxin
20) 2,3,7,8-tetrachlorodibenzodioxin
21) 2,3,7,8-tetrachlorodibenzo(b,e)(1,4) dioxan
22) 2,3,7,8-tetrachlorodibenzo(b,e)(1,4) dioxin
23) 2,3,7,8-tetrachlorodibenzo-p-dioxin
24) 2,3,7,8-tetrachlorodibenzo-1,4-dioxin
25) 2,3,7,8-tetrachloro-p-dioxin
26) Tetradioxin
27) Tetradioxin, D48
28) CAS 1746-01-6

1.2.1) MOLECULAR FORMULA
1) C12-H4-Cl4-O2

Available Forms Sources

1) Dioxins are substituted dioxanes that are extremely toxic by-products of the manufacture of many chemicals (Lewis, 1998). The class of dibenzo-para-dioxins includes 75 isomers (Bingham et al, 2001).
2) In 1983, the EPA canceled registration and prohibited the transfer, distribution, sale, or importation of these compounds. However, stockpiles exist and may be used in limited amounts. 2,4-Dichlorophenol does NOT contain dioxins, although TCDD may be a contaminant of some preparations (Baselt, 1997; NIOSH, 1984).

1) Dioxins are widespread in the environment (Bingham et al, 2001). They do not occur naturally; thus, they are present as a result of man-made (industrial) synthesis (Baxter et al, 2000; ILO, 1998; ATSDR, 1998). Environmental levels peaked around 1970 and have been decreasing since then, mainly because of changes in industrial processes and environmental regulation banning their use (Bingham et al, 2001; EPA, 1994a). Industrial emissions in the year 2002 are expected to be reduced by more than 90% from their levels in the 1980s ((EPA, 2000a)).
2) Dioxins are released into the environment through incineration and combustion, chemical manufacturing processes, processes involving chlorine bleaching or municipal sludge, and recirculation of environmental reservoirs (EPA, 1994a; EPA, 1994b; Johnson, 1995). At present, a significant route of exposure is through the atmospheric fallout of particles and gases contaminated with TCDD (Bingham et al, 2001).
3) Dioxins may be formed during the manufacture of hexachlorophene from 2,4,5-trichlorophenol, pentachlorophenol fungicides and wood preservatives, and from burning pentachlorophenol- or 2,4,5-trichlorophenoxyacetic acid-treated wood. Municipal and medical wastes containing phenol and hydrogen chloride, when burned, can generate dioxins (Eklund et al, 1986).
4) 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic of the 75 dioxins (Lewis, 2000). It is formed as a by-product during many industrial, thermal, photochemical and biochemical processes, in the production of certain chlorinated benzene compounds and polychlorinated phenols (Baxter et al, 2000; Bingham et al, 2001).
5) It is also a toxic by-product and a contaminant of defoliant herbicides such as the once widely used 2,4,5-trichlorophenoxyacetic acid, contained in Agent Orange (Baxter et al, 2000). Formulations of the defoliant 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and 2,4-dichlorophenoxyacetic acid (2,4-D), commonly known as Agent Orange, used in the Vietnam war contained from 0.1 to 30 ppm TCDD (Baselt, 2000).

a) Exposure to TCDD has decreased since the U.S. EPA banned the use of herbicides containing 2,4,5-T in the late 1970s (NTP, 1998).

6) TCDD is also produced during the incineration of hospital and municipal wastes, toxic wastes, with gasoline and other fossil-fuel combustion, in smelters and in paper and pulp bleaching, and it is in wood preservatives (Baxter et al, 2000; Bingham et al, 2001; (EPA, 2000b)). It is considered by some to be the most toxic synthetic compound known (Baxter et al, 2000).
7) Dioxins are also present in cigarette smoke. The total concentration of polychlorinated dibenzo-p-dioxins was approximately 5 mcg/m(3), corresponding to a TEQ of 1.81 ng/m(3). Smoking 20 cigarettes per day would account for an intake of approximately 4.3 pg/kg/day (Muto & Takizawa, 1989).
8) Dioxins have been identified in ceramic clay, or "ball clay", typically used in ceramics and commercial operations (ie, tile, sanitary ware, and miscellaneous ceramics). It is unclear whether the contamination of the clay is the primary route of dioxin exposure or if volatilization of the dioxins occurs during the firing of the clay (Franzblau et al, 2008).

1) The majority of data available is about the isomer 2,3,7,8-tetrachlorodibenzo-p-dioxin. The abbreviation TCDD is often used to refer to this isomer. When the term TCDD is employed in this document, the information refers to the 2,3,7,8-tetrachlorodibenzo-p-dioxin isomer or a sum of the TCDD isomers.
2) Dioxins have no intended commercial use and are not produced intentionally; exposure is through their presence as a by-product or contaminant of certain defoliant herbicides (Baxter et al, 2000; Freeman, 1998; Sittig, 1991). However, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is produced in small quantities for use as a research chemical (Bingham et al, 2001).
3) INTENTIONAL POISONING: A 50-year-old man developed severe toxicity after ingesting a meal containing TCDD (Sorg et al, 2009).
4) TCDD has been tested for use in flame-proofing polyester materials and against insects and wood-destroying fungi (NTP, 2000). There is no evidence that these purposes were ever exploited commercially (ATSDR, 1998).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Dioxins have no intended commercial use; exposure is through their presence as a byproduct or contaminant of certain herbicides. However, 2, 3, 7, 8-tetrachlorodibenzo-p-dioxan (TCDD) is produced in small quantities for use as a research chemical. Dioxins are released into the environment through incineration and combustion, chemical manufacturing processes, processes involving chlorine bleaching or municipal sludge, and recirculation of environmental reservoirs. At present, a significant route of exposure is through the atmospheric fallout of particles and gases contaminated with TCDD.
B) TOXICOLOGY: Dioxins bind to the aryl hydrocarbon receptor protein in cytoplasm, forming a heterodimer with nuclear proteins and inducing transcription of multiple genes. They are mutagenic and act as human carcinogens.
C) EPIDEMIOLOGY: Low-level environmental exposure to dioxins is common. Dioxins have been responsible for several environmental disasters, but exposures rarely produce significant acute toxicity. Deliberate poisoning with dioxins is rare but may cause caustic injury and systemic symptoms.
D) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Acute early signs and symptoms include chemical burns of the skin, irritation of the mucous membranes and eyes, abdominal pain, nausea, vomiting, headache, dizziness, blurred vision, irritability, dyspnea, and severe muscle pains. TCDD affects various hormone systems, particularly sex steroids, corticosteroids, and thyroid hormones. It disrupts normal feedback mechanisms of the pituitary gland. Cardiovascular disorders such as atherosclerosis and myocardial infarction have been suggested but not conclusively shown to be related to TCDD exposure.
2) SEVERE TOXICITY: After a latent period of several weeks, chloracne, an acne-like eruption of the skin, porphyria, cutaneous tarda, hirsutism, and hyperpigmentation may occur. Symptoms (itching, swelling, redness) may occur weeks or months before the eruptions appear and may last a few months or up to 15 years. Polyneuropathies and hepatotoxicity are frequently noted. Increased blood lipids are common and may persist. Pancreatitis, diabetes mellitus, and reduction in cognitive performance have also been noted. There are no known cases of human fatalities from acute exposure to dioxins.
3) CARCINOGENIC EFFECT: TCDD is considered a human carcinogen by IARC.
4) REPRODUCTIVE EFFECT: Dioxins may be human teratogens, specifically for ectodermal dysplasia, CNS, cardiac, and skeletal defects.

0.2.20)

A) Dioxins have not been proven to produce adverse reproductive effects in humans. However, low birth weights, ectodermal dysplasia, and growth and neurological deficits have been associated with dioxin exposure. Data on spontaneous abortions, decreased sperm quality and feminizing alterations of sex hormones have been mixed. TCDD accumulates in breast milk, and neurological deficits and increases in T4 and TSH have been associated with lactational exposure. TCDD is considered an animal teratogen.
B) The US EPA has been re-evaluating the health effects of dioxins. In its current report version ("Draft Final" of May 2000), it is concluded that TCDD is a likely developmental and reproductive toxin.

0.2.21)

A) Dioxins are probable human carcinogens; TCDD is a known human carcinogen. Results are conflicting regarding increased overall cancer morbidity and mortality, and for an association with soft tissue sarcomas, non-Hodgkin and Hodgkin lymphoma. There is limited evidence of an association with myeloma and pulmonary, prostate, gastric, and breast carcinoma. The upper limit for overall risk in the general population may be as high as 1:1000.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF TOXICITY

1) Treatment is symptomatic and supportive following acute exposure.
2) CHLORACNE: Generally resistant to modes of therapy used for acne vulgaris. Acne surgery and dermabrasion have been most beneficial. Topical retinoic acid 0.05% to 0.3% for up to 10 months may be useful. Tetracyclines may be used to treat secondary pustular follicles.
3) BRONCHOSPASM: 100% humidified supplemental oxygen, perform endotracheal intubation and assisted ventilation as required. Beta adrenergic agonists as needed.

B) DECONTAMINATION

1) DERMAL: Remove contaminated clothing and wash exposed area extremely thoroughly with soap and water. Personnel involved in washing patients should wear gloves and avoid contact with contaminated clothing.
2) OCULAR: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persists after 15 minutes of irrigation, and ophthalmologic examination should be performed.
3) ORAL: Gastric lavage: Consider it in the unlikely case of severe acute ingestions if it can be performed soon after ingestion. Activated charcoal: Most exposures are chronic and routine gastrointestinal decontamination is not indicated. In the unlikely event of acute ingestion, administer activated charcoal if conditions are appropriate.

C) AIRWAY MANAGEMENT

1) Endotracheal intubation should be performed in patients with excessive drowsiness and the inability to protect their own airway.

D) ANTIDOTE

1) None.

E) ENHANCED ELIMINATION

1) Elimination may be enhanced through administration of olestra by increasing fecal excretion.

F) PATIENT DISPOSITION

1) OBSERVATION CRITERIA: Patients should be observed in a medical facility until free of acute symptoms. Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
2) ADMISSION CRITERIA: All patients who are acutely symptomatic should be admitted for observation.
3) CONSULT CRITERIA: Consult a medical toxicologist for assistance with any acute exposure or if the diagnosis is unclear.

G) PHARMACOKINETICS

1) Bioavailability is generally unknown and gastrointestinal absorption varies with the vehicle used. Dioxins are lipophilic, found mostly in adipose tissue, skin, liver pancreas and breast milk. TCDD is absorbed by the lymphatic system and is transported by chylomicrons and lipoproteins. Dioxins and TCDD are hepatically metabolized, by cytochrome P450. Excretion is largely fecal. Half-life of TCDD is 5 to 11 years.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Heent

3.4.3)

A) CONJUNCTIVITIS

1) Initial exposure may be accompanied by a burning irritation of the eye and blepharoconjunctivitis (Sittig, 1991; Zenz, 1994).

B) VISION ABNORMAL

1) Exposure may also result in blurred vision (Sittig, 1991).

3.4.5)

A) IRRITATION

1) Inhalation exposure can cause a burning feeling in the nose and throat (Sittig, 1991).

Cardiovascular

3.5.2)

A) CORONARY ARTERIOSCLEROSIS

1) WITH POISONING/EXPOSURE

a) A 15 year follow-up of the Vietnam veterans involved in Operation Ranch Hand, who were exposed to high levels of dioxins as contaminants in Agent Orange during spraying operations between 1962 and 1971, showed an increased number of deaths from diseases of the circulatory system among personnel exposed to the highest levels of dioxin, mainly from atherosclerotic heart disease (Michalek et al, 1998a).

1) At 21 years, coronary atherosclerosis was reported as the second most common cause of death from circulatory diseases in the Vietnam veterans (Ketchum & Michalek, 2005).

b) A study of 5132 US chemical workers, extending an IARC study in 1997, showed a weak increasing trend for heart disease with higher exposure to TCDD (Steenland et al, 1999).
c) Cardiovascular disorders are a consequence of exposure to TCDD (ILO, 1998). Indeed, the heart may be one of the main target organs for TCDD toxicity; decreased beta-adrenergic responsiveness and increased intracellular calcium concentrations were found in guinea pig hearts after exposure (Hayes & Laws, 1991).
d) Advanced progressive atherosclerosis was described in a heavily exposed worker (Pazderova-Vejlupkova et al, 1981). A link between ischemic heart disease and TCDD exposure has been suggested, but not conclusively proven.
e) CASE SERIES: A mortality study of 58 workers showed increased coronary artery disease over the expected US average, but this was not statistically significant (Moses et al, 1984).

B) MYOCARDIAL INFARCTION

1) WITH POISONING/EXPOSURE

a) Data from a 21 year follow-up of Vietnam veterans exposed to high levels of dioxins during Operation Ranch Hand spraying operations between 1962 and 1971 revealed that the most common cause of death from circulatory disease was MI (Ketchum & Michalek, 2005).
b) CASE SERIES: In a 20 year follow-up of 69 workers who developed chloracne due to TCDD exposure, an association between chloracne and death due to myocardial infarction was noted (Dalderup & Zellenrath, 1983).
c) CASE SERIES: An apparent excess of deaths from myocardial infarction was reported among members of a dioxin-exposed clean-up crew (Moses et al, 1984).

Respiratory

3.6.2)

A) DYSPNEA

1) WITH POISONING/EXPOSURE

a) Respiratory tract disorders are a consequence of exposure to TCDD (ILO, 1998). Dyspnea may be noted.

Neurologic

3.7.2)

A) NEUROPATHY

1) WITH POISONING/EXPOSURE

a) Peripheral neuropathy, with sensory impairment, as well as central neuropathy, with lassitude, weakness, impotence and loss of libido, result from exposure to dioxin (Baxter et al, 2000; ILO, 1998). Neuritis and polyneuropathy have occurred after dermal exposure to 2,4-dichlorophenol, with incomplete recovery (Baselt, 1997).
b) Polyneuropathy with sensory impairment and lower extremity weakness is a consistent finding in industrial exposure cases. In mild exposure, asymptomatic alteration in EMG and nerve conduction velocity studies may occur. In severe exposures, about one-third of patients have developed neuropathies (Dunagin, 1984).
c) CASE SERIES: Peripheral neuropathy was reported in 43 of 45 workers involved in a spill of a mixture containing a small amount of dioxin (45 to 46 ppb of TCDD) (Klawans, 1987). The contribution of the main components (phenol and chlorophenol) is unclear.
d) CASE SERIES: Dose-dependent subclinical peripheral neuropathy, defined by the presence of at least 2 bilateral signs or 1 abnormal electrophysiological endpoint, was seen in a group of 152 persons, who also had chloracne, 6 years after the Seveso accident, in which the blowout of a 2,4,5-trichlorophenol production reactor released TCDD over large area in Seveso, Italy, on 10 July 1976 (Barbieri et al, 1988; Schardein, 2000).

B) CRANIAL NERVE FINDING

1) WITH POISONING/EXPOSURE

a) CASE SERIES: Neurological examinations of 119 pesticide plant workers with known exposure to polychlorinated dioxins and furans (33 with chloracne; 84 without chloracne) revealed a higher frequency of brainstem auditory evoked potential (BAEP) abnormalities in the workers with chloracne. Six of the 33 workers with chloracne (18.2%) showed BAEP abnormalities, compared to 7 of the 84 workers without chloracne (8.3%). This difference was not statistically significant (p < 0.15), but the authors feel this is in part due to the small number of workers included in this series (Thomke et al, 2002).

C) DYSTONIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Action dystonias of the hands were reported in 24 of 45 workers involved in the spill of a mixture containing a small amount of dioxin (45 to 46 ppb of TCDD) (Klawans, 1987). The involvement of dioxin is unsubstantiated.

D) HEADACHE

1) WITH POISONING/EXPOSURE

a) Acute exposure by inhalation can produce headache and dizziness (Sittig, 1991).
b) Headaches were reported in a chemist acutely exposed to dioxins (Schecter & Ryan, 1992).

E) ALTERED MENTAL STATUS

1) WITH POISONING/EXPOSURE

a) A reduction of cognitive performance in verbal conceptualization, amnestic organization of verbal and visual stimuli, psychomotor slowing, and subjective complaints such as irritability have been seen on neurologic examination (Peper et al, 1993).

3.7.3)

A) ANIMAL STUDIES

1) NEUROPATHY

a) Polyneuropathy was induced in rats by a single IP dose of 2.2 to 6.6 mcg/kg (Grehl et al, 1993).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH POISONING/EXPOSURE

a) Right-upper-quadrant pain, anorexia, nausea and vomiting have occurred after exposure, but a direct causal link has not been proven (Bingham et al, 2001; Sittig, 1991).
b) Nausea and vomiting may be early symptoms of exposure. However, industrial accidents have involved exposure to other chemicals, and it is likely that these symptoms are not related to TCDD (Young AL, Calcagni JA & Thalken CE et al, 1978).

B) DISORDER OF PANCREAS

1) WITH POISONING/EXPOSURE

a) Pancreatic disorders may be a consequence of exposure to TCDD (ILO, 1998).
b) CASE REPORT: A 57-year-old welder was exposed to dioxins while heating a bearing of an autoclave stirrer. Four days later, he developed acute dermatologic and neurologic symptoms. Within the next 9 months, he was hospitalized twice with enlargement of his liver and pancreas; a large mass of tissue was identified in the right upper quadrant of the abdomen and symptoms of an acute inflammatory process developed. He died approximately 9 months after initial exposure. Pancreatic necrosis, perforation of the stomach and duodenal bulb, liver abscess and chloracne of the trunk were noted on autopsy (Theiss et al, 1982).

Hepatic

3.9.2)

A) CIRRHOSIS OF LIVER

1) WITH POISONING/EXPOSURE

a) A 15 year follow-up of the Vietnam veterans involved in Operation Ranch Hand, who were exposed to high levels of dioxins as contaminants in Agent Orange during spraying operations between 1962 and 1971, showed an increased number of deaths from digestive diseases, mainly chronic liver disease and cirrhosis (Michalek et al, 1998a).

B) LIVER DAMAGE

1) WITH POISONING/EXPOSURE

a) An enlarged liver with impaired function is related to TCDD toxicity (ILO, 1998). Indeed, hepatotoxicity is the most consistent finding in acute occupational exposures, and is manifested by increased liver enzyme activities, mild fibrosis, fatty changes, hemofuscin deposition, parenchymal cell degeneration, and hepatomegaly. In severe exposures, about one-third of patients develop liver damage (Dunagin, 1984).

C) LIVER ENZYMES ABNORMAL

1) WITH POISONING/EXPOSURE

a) Increased serum transaminase levels occur with TCDD toxicity (ILO, 1998). Enzyme induction is prominent in acute and chronic exposure.

D) GAMMA-GLUTAMYL TRANSFERASE RAISED

1) WITH POISONING/EXPOSURE

a) Workers exposed to dioxins who also consume alcohol seem to have a significantly increased risk for an increased serum GGT level. The risk increases with dioxin levels (Calvert et al, 1992).
b) Children exposed in the Seveso accident (in which the blowout of a 2,4,5-trichlorophenol production reactor released TCDD over large area near Seveso, Italy, on 10 July 1976) had increased GGT as well as increased AST and ALT; adults had increased DGA. Clinical evidence of liver disease, however, was lacking (Baxter et al, 2000; Bingham et al, 2001; Schardein, 2000).

Genitourinary

3.10.2)

A) URINARY SYSTEM FINDING

1) WITH POISONING/EXPOSURE

a) Urinary tract disorders may be a consequence of exposure to TCDD (ILO, 1998).

B) HEMORRHAGIC CYSTITIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Hemorrhagic cystitis was reported in a 6-year-old girl chronically exposed to TCDD-containing soil in a horse arena sprayed with contaminated oil. Symptoms resolved within 3 to 4 days (Beale et al, 1977).

C) PORPHYRIA DUE TO TOXIC EFFECT OF SUBSTANCE

1) WITH POISONING/EXPOSURE

a) CASE SERIES: In 11 of 29 patients with dioxin-induced chloracne, urinary uroporphyrins were increased. Concomitant signs and symptoms included 'cola-colored' urine, hyperpigmentation (limited to sun-exposed areas), skin fragility, and hypertrichosis (Bleiberg et al, 1964). After 6 years, none had clinical porphyria and only one had persistent uroporphyrinuria (Poland et al, 1971).
b) The contribution of dioxin was later disputed; hexachlorobenzene was speculated to be the causative agent in some cases (Jones & Chelsky, 1986).

D) ENDOMETRIOSIS (CLINICAL)

1) WITH POISONING/EXPOSURE

a) LACK OF ADVERSE EFFECT

1) One study concluded that based on a critical review of the available literature of both primate and human epidemiologic data, there is no consistent and credible evidence between dioxin exposure and endometriosis. The author suggested further well designed studies with adequate sample size and scientific rigor (Guo, 2004).
2) CASE SERIES: Based on a population-based study in Belgium, 257 subjects (142 women and 115 men) were potentially exposed to environmental dioxins and PCBs. Subjects were obtained from five regions within Belgium, which included living near an iron and steel plant or around a waste dumping site; individuals potentially occupationally exposed to the chemicals were excluded. There was no association between endometriosis and dioxin or PCB exposure as assessed by serum concentrations (Fierens et al, 2003).

Hematologic

3.13.2)

A) PROTHROMBIN TIME LOW

1) WITH POISONING/EXPOSURE

a) PROTHROMBIN TIME PROLONGATION has been noted rarely and may be related to liver damage (Zack & Suskind, 1980).

Dermatologic

3.14.2)

A) CHLORINE ACNE

1) WITH POISONING/EXPOSURE

a) Around 85% to 100% of patients with substantial signs of dioxin toxicity also have chloracne; chloracne is considered the most sensitive indicator of dioxin exposure (Patterson et al, 2016; Dunagin, 1984).

1) However, a small group of people do not manifest chloracne (Pazderova-Vejlupkova et al, 1981). Dioxin toxicity without chloracne has been reported in several instances (Beale et al, 1977; Kimbrough et al, 1977; Oliver, 1975). In a retrospective study, 24% of workers classified as heavily exposed did not have a history of chloracne (Moses et al, 1984).
2) Development of chloracne was related to both intensity and cumulative exposure to tetra-, hexa-, and octachlorinated dioxins in an occupational cohort (Bond et al, 1989b).
3) Lesions may occur in relatives of workers through contact with work clothes, tools, or personal contact.

b) The first sign of reaction of exposed skin is extensive inflammation, resembling lupus erythematosis or erythema elevatum diutinum; photosensitivity may be more or less pronounced (Schulz, 1977).

1) Chloracne consists of an eruption of blackheads with small, pale-yellow cysts on the skin of the face, especially the malar crescent of the eyes and periauricular areas (Patterson et al, 2016; ILO, 1998). Hands and feet are usually spared. Subsequently, the upper chest, back and extremities may become involved. The genitalia may be involved, for males (Hayes & Laws, 1991).
2) Chloracne may be considered a refractory follicular dermatosis (Raffle,1994). The follicular hyperkeratosis of chloracne (with or without cysts and pustules) affects nearly every follicle in involved areas with no intervening normal skin (Hayes & Laws, 1991).
3) Erythema, edema, hirsutism and photosensitivity resulting in eventual hyperpigmentation may occur, although chloracne does occur alone (Hayes & Laws, 1991).

c) Chloracne may appear 2 months after the greatest exposure (Baselt, 2000). However, it usually appears 2 to 4 weeks after initial TCDD contact (Patterson et al, 2016). A delay in onset of 2 to 3 months post-exposure was reported in some men in an industrial accident involving 79 cases of chloracne (May, 1973).

1) Chloracne is usually slowly reversible, subsiding within 1.5 years; it persists for several months in mild cases; severe cases may persist for 30 years or longer (Baselt, 2000; Hayes & Laws, 1991; Moses et al, 1984). Scarring can complicate healing (Hayes, 1982).
2) CASE SERIES: Children and adolescents exposed during the Seveso accident, in which the blowout of a 2,4,5-trichlorophenol production reactor released TCDD over a large area near Seveso, Italy, on 10 July 1976, did not show acneigenesis 2 years after exposure, but atropic scars remained (Caputo et al, 1988; Schardein, 2000).
3) CASE SERIES: Chloracne had cleared after 7 years in all but 1 of 193 persons exposed in the Seveso accident (Assennato et al, 1989).

d) A grading system for chloracne has been developed by the European Economic Community (EEC), as follows (Moses et al, 1984):

1) Grade 1: No change
2) Grade 2: Few comedones in specific sites only
3) Grade 3: More comedones in specific sites, no cysts
4) Grade 4: Numerous comedones in specific sites with cysts
5) Grade 5: Numerous comedones, cysts in specific and other sites
6) Grade 6: Same as grade 4, with inflammatory changes

B) PORPHYRIA CUTANEA TARDA

1) WITH POISONING/EXPOSURE

a) PORPHYRIA CUTANEA TARDA is associated with exposure to TCDD, but only in genetically predisposed individuals (ILO, 1998; IOM, 1993).
b) CASE SERIES: In 11 of 29 patients with dioxin-induced chloracne, urinary uroporphyrins were increased. Concomitant signs and symptoms included 'cola-colored' urine, hyperpigmentation (limited to sun-exposed areas), skin fragility, and hypertrichosis (Bleiberg et al, 1964). After 6 years, none had clinical porphyria and only one had persistent uroporphyrinuria (Poland et al, 1971).

1) The contribution of dioxin was later disputed; hexachlorobenzene was speculated to be the causative agent in some cases (Jones & Chelsky, 1986).

C) KERATODERMA PUNCTATA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 30-year-old woman with severe chloracne from an unidentified exposure to TCDD developed punctate keratoderma-like lesions on the palm of her hands and soles of her feet within months of her original diagnosis. The diagnosis of chloracne was initially made after lab results revealed TCDD blood levels to be 144,000 pg/g blood fat. Treatment with isotretinoin did not help the chloracne or the new palmoplantar lesions. The authors speculate that the very high dioxin level in this patient was responsible for the keratinization disorder (Geusau et al, 2000).

Musculoskeletal

3.15.2)

A) MUSCLE PAIN

1) WITH POISONING/EXPOSURE

a) Myalgia is a common manifestation in acute occupational exposure (Schecter & Ryan, 1992). Neuromuscular effects include severe joint and muscle pain exacerbated by exertion; this mainly affects the calves and thighs and thorax; fatigue and lower-limb weakness also occur (ILO, 1998; Sittig, 1991).

Endocrine

3.16.2)

A) DISORDER OF ENDOCRINE SYSTEM

1) WITH POISONING/EXPOSURE

a) Dioxin has endocrine activity (Harbison, 1998). TCDD affects various hormone systems, particularly sex steroids, corticosteroids and thyroid hormones. It disrupts normal feedback mechanisms of the pituitary gland (Bingham et al, 2001; Kogevinas, 2001).

B) HYPOTHYROIDISM

1) WITH POISONING/EXPOSURE

a) PEDIATRIC: A case series looked at b-TSH levels of infants born to mothers who were exposed to TCDD during the 1976 Seveso, Italy, accident. Women and their children were divided into 3 groups based on exposure area: A, very high contamination area; B, high contamination area; and a reference group from a non-contaminated area.

1) Results showed mean neonatal b-TSH to be significantly higher in populations whose mothers lived in TCDD-contaminated areas during the accident. The reference group's mean neonatal b-TSH was 0.98 microUnits/mL (CI 0.9 to 1.08), Group B's was 1.35 microUnits/mL (CI 1.22 to 1.49), and Group A's was 1.66 microUnits/mL (CI 1.19 to 2.31). The p-value was less than 0.001 for trend across zones. The proportion of infants with b-TSH levels > 5 microUnits/mL was 2.8%, 4.9%, and 16.1% for the reference group, group B, and group A, respectively (p less than 0.001). The authors also found a correlation between maternal plasma TCDD (p less than 0.001) and other coplanar dioxin-like compounds (p=0.005) with neonatal b-TSH (Baccarelli et al, 2008).

C) ABNORMAL GLUCOSE TOLERANCE TEST

1) WITH POISONING/EXPOSURE

a) Pathological changes in glucose tolerance tests occurred in 40% of a group of 80 workers with chronic TCDD exposure (Pazderova-Vejlupkova et al, 1981).

D) DIABETES MELLITUS

1) WITH POISONING/EXPOSURE

a) CASE SERIES: In Vietnam veterans involved in Operation Ranch Hand, who were exposed to high levels of dioxins as contaminants in Agent Orange during spraying operations between 1962 and 1971, the prevalence and severity of diabetes mellitus and the risk of abnormally high glucose increased, and time-to-onset of diabetes decreased, with dioxin exposure (Henriksen et al, 1997).
b) In another study in these veterans, the effect of dioxin body burden on the relation between sex hormone-binding globulin (SHBG) and insulin and fasting glucose was determined. The results suggested a compensatory metabolic relationship between dioxin and insulin regulation (Michalek et al, 1999).
c) However, a study of 5132 US chemical workers exposed to TCDD, extending an IARC study in 1997, showed a negative exposure-response trend for diabetes (Steenland et al, 1999).
d) CASE SERIES: Based on a population-based study in Belgium, 257 subjects (142 women and 115 men) were potentially exposed to environmental dioxins and PCBs. Subjects were obtained from five regions within Belgium, which included living near an iron and steel plant or around a waste dumping site; individuals potentially occupationally exposed to the chemicals were excluded. The findings indicated that diabetic individuals had higher serum levels of dioxins, coplanar PCBs, and the 12 PCB markers. Also, the results indicated a significant increase in the risk of diabetes was found in the most exposed subjects, suggesting a dose-response effect. All parameters remained statistically significant even after adjustment for possible confounders. The authors suggested that further large scale studies are needed to confirm potential causality (Fierens et al, 2003).
e) CASE SERIES: An excess of diabetes mellitus was reported among dioxin-exposed pulp and paper workers (Axelson et al, 1998).

3.16.3)

A) ANIMAL STUDIES

1) ALTERED HORMONE LEVEL

a) DECREASE IN ESTRADIOL RECEPTORS: TCDD exerts its toxicity through the aryl hydrocarbon receptor, a mechanism reminiscent of steroid hormones.

1) Acute treatment of guinea pigs, rats, and hamsters with 4, 50, and 1500 mcg/kg TCDD, respectively, decreased 17 beta-estradiol receptors in the liver by 65% and 92% in guinea pigs and rats, while no change was seen in hamsters. The density of receptors in uteri is inversely related to the lethal dose of TCDD (Hruska & Olson, 1989).

Immunologic

3.19.2)

A) DISORDER OF IMMUNE FUNCTION

1) WITH POISONING/EXPOSURE

a) Some sources consider dioxins to be immunotoxic (Baxter et al, 2000). Further research has suggested the pathogenesis of immune-related diseases by DDT and tetrachlorodibenzo-p-dioxin (TCDD) exposure may occur through the following molecular mechanisms: modulation of intracellular calcium flux, the expression of NF-kB, and proto-oncogenes, or the levels of cyclin, bel-2, and p53 (Forawi et al, 2004).
b) TCDD was shown to suppress T-helper cell function in workers exposed for 20 years (Goldfrank, 1998).

1) A review of animal data concluded that long term TCDD-induced changes appear evident in the immune system after both primary and secondary exposure to dioxin. Its suggested that these findings may have implications for individuals exposed to TCDD who may be immunocompromised (Sherr, 2004).
2) One report states that epidemiological studies have failed to show immunotoxic effects in individuals having other clinical symptoms (Sharma & Reddy, 1987). Of ten studies assessing immune function, only one found a clear association with immunological impairment (Bingham et al, 2001).

c) CASE SERIES: Increased anergy and abnormal T-cell subsets were reported in a group of 154 persons exposed to dioxins in contaminated sludge waste in Missouri (Hoffman et al, 1986). A follow-up study failed to confirm previously reported anergy (Evans et al, 1988).
d) LACK OF ADVERSE EFFECT

1) A study of the Vietnam veterans involved in Operation Ranch Hand, who were exposed to high levels of dioxins as contaminants in Agent Orange during spraying operations between 1962 and 1971, failed to demonstrate a consistent relationship between the level of exposure to dioxin and immune system alteration (Michalek et al, 1999a).
2) TCDD failed to alter surface marker distribution or suppress human lymphocyte proliferation in vitro (Lang et al, 1994).

3.19.3)

A) ANIMAL STUDIES

1) IMMUNOGLOBULINS DECREASED

a) SUPPRESSED HUMORAL ANTIBODIES: IgM antibody response to sheep red blood cells was suppressed in mice exposed subchronically to dioxin (Holsapple et al, 1984).
b) Depression of humoral immunity (antibody plaque-forming response to sheep erythrocytes) was a more sensitive endpoint than cellular immunity (cytotoxic T lymphocyte response to P815 mastocytoma cells) in mice given intraperitoneal injections of 1 and 3 mcg/kg/week of TCDD (Hanson & Smialowicz, 1994).
c) TCDD inhibited differentiation of mouse B cells into antibody-secreting cells in vitro. Inhibition in congenic strains correlated with aryl hydrocarbon receptor activity (Tucker et al, 1986).
d) In contrast to results in mice, TCDD enhanced humoral immunity in rats when given in single intraperitoneal injections at 1 to 30 mcg/kg; these doses were sufficient to induce cytochrome P450 1A1 and 1A2 (Smialowicz et al, 1994).

2) ENDOCRINE DISORDER

a) THYMIC ATROPHY has been demonstrated in every mammalian species tested (Anon, 1988).

1) Thymic and splenic atrophy were acute responses in rats fed TCDD at levels up to 1 ppm in the diet for 78 weeks (VanMiller et al, 1977).

3) IMMUNE SYSTEM DISORDER

a) Mice exposed to TCDD pre- and postnatally had bone marrow hypocellularity, depressed macrophage-granulocyte progenitor and stem cell colony formation, depressed lymphoproliferative responses, and increased susceptibility to bacterial or tumor challenge (Luster et al, 1980).

Reproductive

3.20.1)

3.20.2)

A) CONGENITAL ANOMALY

1) There is no conclusive evidence that dioxins cause birth defects in humans (Erickson et al, 1984; IOM, 1993; Pearn, 1985). This is because various reports involved mixed exposures, poorly documented exposures, or inconsistent patterns of abnormalities. The controversy continues about whether dioxins are human teratogens; TCDD is considered developmentally toxic by California Proposition 65 (Schardein, 2000).

a) Of the 31 published studies on human reproductive effects of dioxin (combined with 2,4-dichlorophenol and 2,4,5-trichlorophenoxyacetic acid) reviewed by Hayes & Laws (1991), 10 showed positive effects and 21 were negative. Of the studies with negative associations overall, 4 had positive associations in subsets of groups or data.
b) However, TCDD is considered an animal teratogen, producing both developmental and reproductive toxicity (Baxter et al, 2000; Bingham et al, 2001).
c) The US EPA has been re-evaluating the health effects of dioxins. In its report version ("Draft Final" of May 2000), it is concluded that TCDD is a likely developmental and reproductive toxin. The level at which these effects may be experienced remains unclear ((EPA, 2000a)).

2) Studies of Vietnam veterans involved in Operation Ranch Hand, the unit responsible for aerial spraying of herbicides in Vietnam between 1962 and 1971, have provided little support for the theory of a connection between adverse reproductive effects and paternal exposure to Agent Orange and its dioxin contaminants (Michalek et al, 1998b; Wolfe et al, 1995).

a) Increased nervous system defects were seen in children of Vietnam veterans involved in Operation Ranch Hand, but these were based on sparse data (Wolfe et al, 1995). However, increased rates of fetal loss before 20 weeks, and skeletal, CNS and cardiovascular malformations were seen in a group of 832 Tasmanian Vietnam veterans' families (Field & Kerr, 1988).
b) Other studies have failed to find an association between exposure to dioxins in Vietnam and increased rates of birth defects through paternally mediated effects (Erikson et al, 1984; (Walsh et al, 1983).

3) A study of Canadian saw-mill workers exposed to chlorophenols contaminated with TCDD found an association between male exposure and the occurrence of eye, neural tube and genital malformations (Dimich-Ward et al, 1996).
4) Lower psychomotor scores at 3 months of age were correlated with higher prenatal exposures to TCDD and not to PCB's, determined as maternal levels during the last month of gestation; this difference disappeared by 18 months of age (Koopman-Esseboom et al, 1996).
5) Neurological development of a group of Dutch infants was negatively affected to a slight extent by prenatal, but not by lactational, exposure to dioxins (Huisman et al, 1995).

B) GROWTH RETARDED

1) Lower birth weights have been seen in offspring of women living on the east coast of Sweden, where the diet is rich in fish contaminated with persistent organochlorine compounds from the Baltic Sea (Rylander & Hagmar, 1995).
2) Lower birth weights and lengths were also seen in offspring of 221 teachers exposed to dioxins, dibenzofurans, lindane and pentachlorophenol in indoor air (Karmaus & Wolf, 1995). Because of mixed exposures, these effects could not be attributed specifically to TCDD. They were ascertained not to be due to shorter gestational age, and were therefore possibly due to a direct toxic effect on pregnancy.
3) Two early episodes of 'Yusho' or 'Yucheng' disease ('oil disease') involved contaminated cooking oil in Fukuoka Prefecture, Japan, in 1968 and Yu-Cheng, Taiwan, in 1979 (Hayes & Laws, 1991; Schardein, 2000).

a) The contaminants were dioxins and/or dioxin-like compounds including PCBs, chlorodibenzofurans, and quarterphenyl TCDD, formed from heating of PCBs. The toxic effects were thought to be due mainly to dibenzofurans (Schecter et al, 1994).
b) Offspring had an odd 'cola' skin color and minor skeletal anomalies (Schardein, 2000). Reproductive effects included ectodermal dysplasia, clustered in organs derived from the ectodermal germ layer, including skin, nails, and meibomian glands. Developmental and psychomotor delay and growth retardation were also present, and persisted throughout childhood (Chen et al, 1992; Guo et al, 1994; Hsu et al, 1993; Lai et al, 1993).

4) Studies of Vietnam veterans of Operation Ranch Hand did not demonstrate an increased risk of intrauterine growth retardation associated with paternal exposure to dioxins (Michalek et al, 1998b).

C) LACK OF EFFECT

1) About 2900 kg organic matter and 1.5 to 2 kg TCDD were released over a 700-acre area of urbanized land near Seveso, Italy, on 10 July 1976, when a runaway exothermic reaction led to a blowout of a 2,4,5-trichlorophenol production reactor (Baxter et al, 2000; Bingham et al, 2001; Schardein, 2000).

a) A study of births after the Seveso accident showed no increased risk of malformations; however, the number of exposed fetuses was too low to detect a small increased teratogenicity risk (Mastroiacovo et al, 1988).
b) One investigator reported an increase in the rate of malformations in the Seveso area, from 0.13% before the accident to 0.87% when exposed women would have delivered, but there was no consistency as to the types of malformations seen (Reggiani, 1978).
c) A later study of 999 pregnancies in low-exposure areas and 203 in moderate-exposure areas showed a statistically significant increase in cardiovascular, genitourinary and skeletal abnormalities 18 to 30 months after moderate exposure (Schardein, 2000).
d) However, no major malformations were found by a study of the birth registry of the most-contaminated area for births January 1977 to December 1982. It was concluded that the data failed to show an increased risk of birth defects related to dioxin, although controversy over the hazardous effects of this exposure continue (Schardein, 2000).

2) No increases in cleft lip or palate were seen among families living nearby after initiation of waste incineration in Sweden (Jansson & Voog, 1989). In a study of 930 male chlorophenol workers and their wives, no adverse reproductive outcomes were found compared with an unexposed group (Townsend et al, 1982).

D) ANIMAL STUDIES

1) TCDD is an extremely potent teratogen in rodents. Although results have varied, it shows teratogenicity in mice, rabbits, hamsters and ferrets, equivocal results in rats, and negative results in primates (Schardein, 2000; ILO, 1998). Effects on the developing fetus have been demonstrated at doses more than 100 times lower than those producing maternal toxicity (Bingham et al, 2001).
2) TCDD is teratogenic in various strains of mice (Courtney & Moore, 1971). Indeed, the mouse is the most sensitive experimental system for studying the teratogenic effects of TCDD; all mouse studies demonstrate teratogenicity (Couture et al, 1990; Schardein, 2000).

a) In mice, TCDD has reportedly produced developmental abnormalities of the craniofacial, immune, reticuloendothelial, urogenital, endocrine and musculoskeletal systems, as well as fetal death and post-implantation mortality (RTECS , 2001).
b) Decreased developmental rates were noted in mouse embryos after exposure to 1 to 5 ppm TCDD (Tsutsumi, 2000).
c) DBA/2J mice, which are resistant to the induction of cytochrome P450 by TCDD, were 2 to 3 fold more resistant to induction of hydronephrosis and cleft palate than the C57BL/6J strain (Hassoun & Stohs, 1996).
d) An increased incidence of cleft palate and hydronephrosis was seen in mouse studies with TCDD (Birnbaum et al, 1991). Thymic hypoplasia is also a characteristic finding in mice exposed prenatally to TCDD (Couture et al, 1990).
e) Cleft palate and dilated renal pelvis were seen in fetal mice exposed to 3 mcg/kg/day TCDD by oral gavage on days 6 to 15 of gestation, and cleft palate was noted at a dose of at 1 mcg/kg/day (Smith et al, 1976).
f) No effects on teratogenicity or development were seen in offspring of male mice exposed to 2.4 mcg/kg TCDD in the diet for 8 weeks (mixed with 2,4-dichlorophenol and 2,4,5-trichlorophenoxyacetic acid) and mated with untreated females (Lamb et al, 1981b).

3) In rats, TCDD produced developmental abnormalities of the endocrine, urogenital, and blood and lymphatic systems, and also produced fetal death and stunted fetuses (RTECS , 2001). In rabbits, it produced developmental abnormalities of the musculoskeletal and urogenital systems, and abortions, pre-implantation mortality and fetal death (RTECS , 2001). Cognitive deficits have been reported in monkeys exposed perinatally to dioxins (Schantz & Bowman, 1989).
4) The relative susceptibility of guinea pigs, rats, and hamsters for induction of hydronephrosis was roughly similar, in contrast to their differing sensitivity for acute toxicity of TCDD (Olson & McGarrigle, 1992).

a) This is also true for different strains of rats. Single doses of TCDD in the range of 1 to 10 mcg/kg produced malformations in both Long-Evans and Han/Wistar rats, but the acute LD50s in these two strains differ by 1000 fold (Huuskonen et al, 1994).
b) The spectrum of effects was different in the two strains of rats. Cleft palate occurred in more than 70% of live Long-Evans fetuses exposed to 5 mcg/kg on day 8 or 12 of gestation. Hydronephrosis and gastrointestinal hemorrhaging were produced in the Han/Wistar fetuses (Huuskonen et al, 1994).

5) Other dioxin-like compounds, 2,3,7,8-tetrachlorodibenzofuran and 3,3',4,4'-tetrachloroazoxy benzene, were also teratogenic in mice and produced similar types of defects seen with TCDD, but with a lower potency, corresponding to their relative affinities for the aryl hydrocarbon receptor (Abdul Malek Hassoun, 1985).
6) Sprague-Dawley rats exposed orally to 1 mcg TCDD/kg on either gestational day (GD) 15, GD 18 and postnatal day (PND) 2 revealed significant decreases in the urogenital complex and ventral prostate weights and urogenital-glans penis length of male offspring of rats exposed on GD 15 only (Ohsako et al, 2002).
7) Exposure of adult rainbow trout to TCDD at concentrations comparable to current environmental concentrations (females fed 1.8 ng TCDD/kg) adversely affected survival of the fry (Giesy et al, 2002).

3.20.3)

A) PLACENTAL BARRIER

1) There is limited transplacental transfer of TCDD to the fetus (Hayes & Laws, 1991). The placental transport of dioxins from mother to fetus that has been shown to occur is probably related to fatty acid transport (Koppe et al, 1992). A study of pregnant women in Japan suggested that placental transfer differs depending on the dioxin congener (Nakano et al, 2005).

B) ABORTION

1) Studies of Vietnam veterans involved in Operation Ranch Hand, the unit responsible for aerial spraying of herbicides in Vietnam between 1962 and 1971, showed no meaningful increase in the risk for spontaneous abortion or stillbirth associated with paternal exposure to Agent Orange and its dioxin contaminants (Wolfe et al, 1995).
2) In a previous study, a small but statistically significant increase in miscarriage rate was noted in women whose mates were exposed to Agent Orange in Vietnam (Stellman et al, 1988). A study of residents of Times Beach, Missouri, who were exposed to dioxin after roads were sprayed with TCDD-contaminated waste oil for dust control, failed to confirm this (Stockbauer et al, 1988).
3) Apparent clusters of spontaneous abortions related to spraying 2,4,5-trichlorophenoxyacetic acid in forestry operations near Alsea, Oregon, were studied by the US EPA. A second EPA study claimed an association between miscarriages and spraying, but it has been strongly criticized because of failure to follow accepted epidemiological methods (discussed in AMA, 1981).
4) Studies of pregnancy outcomes in Seveso showed that abortion rates after the blowout of a 2,4,5-trichlorophenol production reactor released TCDD over large area were comparable to the expected rates in other, non-exposed areas (Schardein, 2000).

C) PREGNANCY DISORDER

1) More complications of pregnancy were seen in a group of Tasmanian Vietnam veterans' wives than in a comparison group (Field & Kerr, 1988).

D) STILLBIRTH

1) A study of the Vietnam veterans of Operation Ranch Hand showed an increased risk of preterm death for offspring in both the 'high' and 'background' exposure categories; the authors concluded this risk might not be linked to the paternal dioxin level (Michalek et al, 1998b). Another study found no meaningful increase in the risk of stillbirth (Wolfe et al, 1995).

E) LACK OF EFFECT

1) Studies in Seveso of 623 women pregnant (one-third in the first trimester) at the time of the accident showed that this TCDD exposure produced no unusual incidence of prenatal or postnatal mortality, and the offspring born showed no ill effects (Hayes & Laws, 1991; Schardein, 2000).

F) ANIMAL STUDIES

1) TCDD is lethal to embryos or fetuses of mammals, birds, and fish at doses which are not maternally toxic (EPA, 1994b).
2) Smaller litter sizes, increased neonatal mortality, and reduced growth rates were seen in F2 and F3 generations of rats fed 0.01 mcg/kg/day TCDD (Murray et al, 1977).
3) Increased pre- and post-implantation loss and fetal growth retardation were seen in rats receiving 0.5 to 2 mcg/kg/day by gavage for 2 weeks prior to mating (Giavini et al, 1983).
4) TCDD has been shown to produce cardiovascular toxicity in piscine, avian and mammalian embryos. One study revealed a possible mechanism to be reduction in myocyte proliferation and subsequent thinner ventricle wall (Ivnitski et al, 2001).

3.20.4)

A) BREAST MILK

1) TCDD is lipophilic, therefore it accumulates in breast milk (Baxter et al, 2000).

a) Nursing infants are a group at highest risk for exposure to dioxins. One survey of 42 US mothers found an average of 16 pg TEQ/gram (16 ppt) in the lipid fraction of breast milk, of which only 3.3 ppt was due to TCDD (Schecter et al, 1992). Breast milk from German mothers had even higher levels, averaging 31 ppt (Beck et al, 1991).
b) Levels as high as 1832 ppt were seen in breast milk fat collected from South Vietnamese women in 1970 (Schecter et al, 1995). Samples of human milk from areas in Vietnam heavily treated with 2,4,5-trichlorophenoxyacetic acid were analyzed in 1974 and found to contain 40 to 50 ppt of TCDD. No TCDD was detected in milk from residents of West Texas where heavy spraying for brush control occurred (Schecter et al, 1995).
c) Lorber et al (2002) used a one-compartment, first-order pharmacokinetic model to evaluate dioxin burden to the infant from breast-feeding. It was found that an infant breast-fed for 1 year had an accumulated dioxin exposure 6 times higher than a 1-year-old who had been formula fed (Lorber & Phillips, 2002).
d) In one study, dioxin concentrations in the milk fat of breast milk in 14 mothers were found to be 80 to 132 ppt, close to or in the range necessary to induce liver enzymes. The authors suggest the possibility that enzyme induction in these babies may result in vitamin K deficiency, resulting in bleeding (Koppe, 1989).
e) A Japanese study of 151 pregnant women found that dioxin total equivalents in breast milk were approximately 30% lower in women who took Chorella pyrenoidosa supplements (a unicellular green algae that grows in fresh water; contains vitamins, minerals, dietary fibers and nucleic acids) during pregnancy, compared with controls who did not take the supplement (Nakano et al, 2005).
f) NEUROLOGICAL DEFICITS - Neonatal neurological deficits, determined by the Prechtl neurological examination, were related to concentrations of 17 dioxin congeners and other dioxin-like compounds in breast milk measured 2 weeks post-partum in a group of 209 breast-fed Dutch infants (Huisman et al, 1995).

B) THYROID DISORDER

1) Significant increases in total thyroxine (T4) and thyrotropin (TSH) levels were seen in infants, in relation to dioxin concentrations in the milk fat of their mothers (Pluim et al, 1992; Pluim et al, 1993).

C) ANIMAL STUDIES

1) Adult rats were immunosuppressed after exposure to TCDD through the nursing mothers (Badesha et al, 1995).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS1746-01-6 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) IARC Classification

a) Listed as: 2,3,7,8-Tetrachlorodibenzo-para-dioxin
b) Carcinogen Rating: 1

1) The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.

3.21.2)

3.21.3)

A) LACK OF INFORMATION

1) There is INADEQUATE/INSUFFICIENT EVIDENCE to determine whether an association exits between dioxin exposure and the following cancers (IOM, 1993):

a) Nasal/nasopharyngeal cancer
b) Neoplasm
c) Bone cancer
d) Cervical cancer and female reproductive cancers
e) Renal cancer
f) Testis neoplasm, malignant

2) There is LIMITED/SUGGESTIVE EVIDENCE OF NO ASSOCIATION of the following cancers and dioxin exposure (IOM, 1993):

a) Skin cancer
b) Bladder cancer
c) Brain tumors

1) Increased deaths from brain cancer were seen 10 years after the Seveso accident, in which the blowout of a 2,4,5-trichlorophenol production reactor released TCDD over a large area near Seveso, Italy, in 1976, but they were not dose-related (Bertazzi et al, 1989).

B) CARCINOMA

1) OVERALL CANCER MORBIDITY AND MORTALITY: TCDD is a known human carcinogen (Bingham et al, 2001; IARC , 1997; Kogevinas, 2001). The upper limit for overall risk for human cancer among the general population may be as high as 1:1000 (EPA, 1994b; Johnson, 1995). Evidence is strong for an association with soft tissue sarcomas; Hodgkin disease and non-Hodgkin lymphoma have been linked more with dioxin-contaminated chlorphenoxy herbicides (IOM, 1993).
2) Several studies have shown associations between dioxin exposure and increased risk of cancer morbidity and mortality:

a) IARC reported an increased risk for all cancers combined in a group of cohorts from the US, the Netherlands, Germany and Seveso, Italy, with a higher increase in risk in those suffering the heaviest exposure (IARC , 1997).
b) A study of 5132 US chemical workers, extending that 1997 IARC study, showed an excess of all cancers combined limited to workers exposed to 100 to 1000 times the levels of TCDD experienced by the general population (Steenland et al, 1999). Overall cancer mortality was highest in a group of German workers with highest exposure to dioxins (Becher et al, 1996).
c) Dose-dependent increases in risk of mortality from all cancers were seen in a retrospective cohort of 1189 male chemical workers exposed to TCDD and other higher chlorinated dioxins and furans. The highest relative risk was 3.30 in the highest decile. Quantitative exposures were obtained from analysis of blood and adipose tissue (Fleschjanys et al, 1995).
d) A retrospective cohort study of 1583 workers potentially exposed to dioxin showed an increased rate of cancer mortality in men with more than 20 years of employment in the chemical plant (Manz et al, 1991).
e) A retrospective cohort study of mortality among 5172 workers potentially exposed to dioxin showed excess mortality from all cancers combined, cancers of the respiratory tract and soft-tissue sarcoma. The possible contribution of factors such as smoking and occupational exposure to other chemicals cannot be excluded (Fingerhut et al, 1991).
f) Increased deaths from cancers were seen in a group of 74 persons after acute exposure to dioxin in an industrial accident (7 observed versus 4.1 expected) (Thiess et al, 1982).

3) Other studies have found no association between dioxin exposure and cancer mortality:

a) A study of the Vietnam veterans involved in Operation Ranch Hand, who were exposed to high levels of dioxins as contaminants in Agent Orange during spraying operations between 1962 and 1971, showed no statistically significant increase in cancer risk in the group categorized as having the highest dioxin exposure (Ketchum et al, 1999).
b) A 15 year follow-up of these Operation Ranch Hand veterans also showed no significant increase in the risk of death from cancer at all sites, as well as a nonsignificant increase in the number of deaths from bronchus and lung cancer (Michalek et al, 1998a).
c) US Vietnam veterans have a 50% increased risk for non-Hodgkin lymphoma, but it is not apparently related to exposure to dioxins. Moreover, they do not seem to be at increased risk for soft tissue or other sarcomas, liver cancer, Hodgkin disease, or nasal or nasopharyngeal cancer (10).
d) A 15 year study of cancer risk in Seveso, after the 1976 blowout of a 2,4,5-trichlorophenol production reactor released TCDD over large area, found no increase in all-cancer mortality or major specific sites (respiratory for males; breast for females) (Bertazzi et al, 1997).
e) No increase in deaths due to all cancers was seen in a cohort study of 2192 potentially exposed chemical workers (Bond et al, 1989a; Ott et al, 1987).
f) Deaths from all causes, all cancers, or any specific cancer were not significantly increased in 963 Dutch workers who had been occupationally exposed to TCDD, or in a subset of 139 who probably had higher-level acute exposure during a production accident involving 2,4,5-trichlorophenol (de Mesquita & Doornbos, 1993).
g) No excess deaths from cancer were seen in a group of 121 workers thought to be exposed to TCDD in an industrial accident in West Virginia nearly 30 years previously. Exposure was presumed from development of chloracne (Anon, 1980).

4) A review of the EPA's assessment of dioxin as a cause of cancer found that in fact dioxin is a promoter blocker of certain cancers, including those previously considered by the EPA to be promoted by dioxin, a promoter of some cancers not identified by the EPA, and, overall, a net anticarcinogen (Kayajanian, 1997).
5) Dioxin (as TCDD) may have chemoprotective properties; its aryl hydrocarbon receptor turns off proliferation in tumor cells and suppresses their ability to invade normal tissue (Greenlee et al, 2001).

a) Two New Zealand cohorts of 1025 phenoxy herbicide producers and 703 sprayers were followed from January 1, 1969 and January 1, 1973, respectively, to December 31, 2000. Calculation of standardized mortality rates (SMR) revealed a non-significant excess of cancer related deaths of 24% in the producer cohort with a significant excess of multiple myeloma (SMR=5.51). All cancer mortality was higher in the producers involved in product synthesis. In the sprayer cohort, total cancer mortality was decreased compared to the production workers with increased mortality from colon and other gastrointestinal cancers (SMR=1.94) ('t Mannetje et al, 2005).

C) SARCOMA

1) There is reportedly sufficient evidence of an association between dioxins and the development of soft-tissue sarcoma, with a 2 fold increase reported in a 1997 IARC study of 30,000 dioxin-exposed workers in 12 countries (ILO, 1998; IOM, 1993).

a) A 15 year study of cancer risk in Seveso, after the 1976 blowout of a 2,4,5-trichlorophenol production reactor released TCDD over large area, found an increase in soft-tissue sarcoma only in males in the area of lowest exposure (Bertazzi et al, 1997).
b) A retrospective cohort study of mortality among 5172 workers potentially exposed to dioxin showed excess mortality from all cancers combined and soft-tissue sarcoma. The possible contribution of factors such as smoking and occupational exposure to other chemicals cannot be excluded (Fingerhut et al, 1991).
c) Nonsignificant increases in deaths from soft-tissue sarcoma (n=4) were seen 10 and 19 years after first occupational exposure in an IARC cohort of 18,910 production workers or sprayers exposed to chlorophenoxy herbicides (Saracci et al, 1991).
d) Eriksson et al (1990) found an increased risk for soft-tissue sarcoma in a population-based case control study (Eriksson et al, 1990).
e) Sarcomas were attributed to TCDD exposure in several small case-control studies in Sweden; however, exposure to other chemicals (chlorophenols and phenoxyherbicides) was evident (Cook, 1981; Hardell, 1979; Hardell & Sandrom, 1979; Hardell & Eriksson, 1988; Honchar & Halperin, 1981).
f) An increased risk for soft-tissue sarcoma was seen in relation to exposure to TCDD (OR=5.2) and polychlorinated dibenzodioxins or furans (OR=5.6) in two nested case-control studies. The risk was higher for exposure to any phenoxy herbicide, however (OR=10.3) (Kogevinas et al, 1995).

2) Other studies have shown no association between soft-tissue sarcomas and dioxin exposure:

a) Increased mortality from soft-tissue sarcoma was seen in a group of 754 persons occupationally exposed to 4-aminobiphenyl and TCDD in an industrial accident, but not in those thought to be exposed to TCDD alone (Collins et al, 1993).
b) Two larger case-control studies involving a total of 363 sarcoma patients found no relationship with occupational exposure to phenoxyherbicides, chlorophenols, or exposure to herbicides used in Vietnam (Greenwald et al, 1984; Smith et al, 1984).

3) The latency period for soft-tissue sarcoma in adults is probably long; many years of observation will be necessary before more-conclusive evidence can be obtained (Kogan & Clapp, 1988).

D) LYMPHOMA-LIKE DISORDER

1) There is reportedly sufficient evidence for an association of lymphoma-like disorders with herbicides (IOM, 1993).
2) There was a significant increase in morbidity related to malignant lymphoma in 105 cases exposed to phenoxy acids or chlorophenols (Hardell, 1981).
3) Studies on NON-HODGKIN LYMPHOMA have produced conflicting results:

a) Most studies reported by IARC have shown a nonsignificant increased risk for non-Hodgkin lymphoma (IARC , 1997). The increased rate of non-Hodgkin lymphoma was especially true for workers exposed to TCDD-contaminated herbicides (ILO, 1998).
b) Increased deaths from non-Hodgkin lymphoma were seen in a cohort of 2479 German workers who were exposed to dioxins and phenoxy herbicides (Becher et al, 1996).
c) The association between phenoxy herbicides (and TCDD specifically) and non-Hodgkin lymphoma was lower than the risk for soft-tissue sarcoma in two nested case-control studies of an international cohort (Kogevinas et al, 1995).
d) Some data show an increased risk for non-Hodgkin lymphoma in persons exposed to dioxins and not to phenoxy herbicides. The relative risk for morbidity from non-Hodgkin lymphoma was 3.5 in the least-exposed persons Seveso, after the 1976 blowout of a 2,4,5-trichlorophenol production reactor that released TCDD over large area. This study did not show a clear dose-response, however (Bertazzi et al, 1993).
e) Floret et al (2003) compared 222 cases of non-Hodgkin lymphoma diagnosed between 1980 and 1995 to controls randomly selected from the 1990 population census (10 to 1 match) in an area surrounding a French solid waste incinerator with known dioxin emissions. Statistical analysis found that individuals residing in the highest dioxin-exposure zone were 2.3 times more likely to develop non-Hodgkin lymphoma (CI 1.4 to 3.8) than those living in the very low emission areas (Floret et al, 2003).
f) No significant increases in non-Hodgkin lymphoma were found in large studies on occupationally exposed persons (Fingerhut et al, 1991; Manz et al, 1991; Saracci et al, 1991; Zober et al, 1990).

1) A significant increase in morbidity related to non-Hodgkin lymphoma was found in a study 106 cases exposed to phenoxy acids (Persson et al, 1989). Increased but nonsignificant risks for non-Hodgkin lymphoma were found in studies of farmers and agricultural workers exposed to the herbicide 2,4-dichlorophenoxyacetic acid (Hoar et al, 1986; Zahm et al, 1990).
2) Because these would have been the most heavily TCDD-exposed groups, the evidence suggests that the association with non-Hodgkin lymphoma is due to PHENOXY HERBICIDES, not dioxins (IOM, 1993). Refer to CHLORPHENOXY COMPOUNDS MEDITEXT(R) medical management for further information.

4) For HODGKIN DISEASE, there is reportedly sufficient evidence of an association with HERBICIDES (IOM, 1993). Studies relating Hodgkin disease with dioxin exposure and/or herbicides have had mixed results:

a) A 15 year study of cancer risk in Seveso after the 1976 accident found an increase in hematological neoplasms; one of the highest risks was Hodgkin disease in both men and women, in the area of lower exposure (Bertazzi et al, 1997).
b) A suggestive increase in incidence of Hodgkin disease occurred during the first 10 years after the Seveso accident in the youngest segment of the exposed population (Pesatori et al, 1993).
c) Nearly all of the 13 case-control and occupational studies have shown an association between exposure and Hodgkin disease, but not all results have been statistically significant (IOM, 1993). The occupational groups most heavily exposed to dioxins did NOT show an increase in Hodgkin disease, however (IOM, 1993).
d) In a group of 60 patients, there was a dose-related risk for development of Hodgkin disease in relation to exposure to chlorophenols (which may contain dioxins as contaminants) (Hardell et al, 1981; Hardell & Bengtsson, 1983). A nonsignificant association between exposure to phenoxy acids and Hodgkin disease was seen in a cohort of 54 cases (Persson et al, 1989).

E) MYELOMA

1) There is limited/suggestive evidence of an association of dioxin exposure and myeloma (IOM, 1993). Increased risk for multiple myeloma has been reported after occupational exposure to TCDD (IARC, 1977).
2) A 15 year study of cancer risk in Seveso, after the 1976 blowout of a 2,4,5-trichlorophenol production reactor released TCDD over large area, found an increase in hematological neoplasms; one of the highest risks was multiple myeloma in women in the area of lower exposure (Bertazzi et al, 1997).
3) The relative risk for morbidity from multiple myeloma among women with intermediate exposure in the Seveso accident was 5.3 after 10 years (Bertazzi et al, 1993).
4) Of 10 studies of forestry and agricultural workers exposed to dioxins in herbicides (and possibly as by-products of burning), all showed an elevated risk for multiple myeloma. The association was statistically significant in seven of these studies (IOM, 1993).
5) Stratification of exposure groups has shown increased risk with herbicide (with dioxin contaminant) exposure (Alavanja et al, 1989; Boffetta et al, 1989; Burmeister et al, 1983; Cantor & Blair, 1984).

F) LEUKEMIA

1) There is inadequate/insufficient evidence to determine whether or not an association exits between dioxin exposure and leukemia (IOM, 1993).
2) A 15 year study of cancer risk in Seveso, after the 1976 blowout of a 2,4,5-trichlorophenol production reactor released TCDD over large area, found an increase in hematological neoplasms; one of the highest risks was leukemia in men in the area of lower exposure (Bertazzi et al, 1997).
3) Increased deaths from leukemias were seen 10 years after the Seveso accident, but they were not dose-related (Bertazzi et al, 1989). The relative risk for morbidity from myeloid leukemia was 3.7 among women living in the zone of intermediate exposure (Bertazzi et al, 1993). The incidence of myeloid leukemia was increased in the youngest population segment 10 years after exposure, but this increase was not statistically significant (RR=2.7) (Pesatori et al, 1993).

G) PULMONARY CARCINOMA

1) There is limited/suggestive evidence of an association of dioxin exposure and pulmonary carcinoma (IOM, 1993). Workers exposed to TCDD had an increase in cancer mortality from respiratory cancer (Goldfrank, 1998).
2) Increased deaths from cancers of the respiratory tract (SMR=154) and buccal cavity/pharynx (SMR=295) were seen in a cohort of 2479 German workers exposed to dioxins and phenoxy herbicides (Becher et al, 1996).
3) A retrospective cohort study of mortality among 5172 workers potentially exposed to dioxins showed excess mortality from all cancers combined and cancers of the respiratory tract. The possible contribution of factors such as smoking and occupational exposure to other chemicals cannot be excluded (Fingerhut et al, 1991).
4) Other occupational cohorts heavily exposed to TCDD have also shown an increase in respiratory cancers (Manz et al, 1991; Saracci et al, 1991; Zober et al, 1990).
5) Herbicide applicators have also shown an increase in respiratory tract cancers (Axelson & Sundell, 1974; Blair et al, 1983) Green, 1991; (Riihimaki et al, 1982).

H) PROSTATE CARCINOMA

1) There is limited/suggestive evidence of an association of dioxin exposure and prostate cancer (IOM, 1993).
2) A historic cohort study of veterans found that exposure to Agent Orange contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin is associated with an increased risk of prostate cancer, especially high-grade prostate cancer (Gleason score of 7 or higher). Of the 2720 veterans who underwent a prostate biopsy, prostate cancer was detected in 896 men (32.9%), and 459 men (16.9%) had high-grade prostate cancer. The risk of prostate cancer was 52% higher (adjusted odds ratio [OR], 1.52; 95% CI, 1.07 to 2.13) in men with Agent Orange exposure (n=203) compared with those who had no exposure (n=2517). While Agent Orange exposure had no significant association with risk of low-grade prostate cancer (adjusted OR, 1.24; 95% CI, 0.81 to 1.91), a significant association was observed between exposure and risk of high-grade prostate cancer (adjusted OR, 1.75; 95% CI, 1.12 to 2.74). An even stronger association of 2.1 fold was shown between Agent Orange exposure and risk of detecting prostate cancer with a Gleason score of 8 or higher (adjusted OR, 2.1; 95% CI, 1.22 to 3.62) (Ansbaugh et al, 2013).
3) Increased risk of prostate cancer in Canadian farmers was associated with herbicide spraying (Morrison et al, 1993).
4) Because prostate cancer is one of the most common cancers and is increasingly prevalent with age, the likelihood of finding a clear-cut association with any exposure is small.

I) HEPATIC CARCINOMA

1) There is reportedly inadequate/insufficient evidence to determine whether or not an association exits between dioxin exposure and liver cancer (IOM, 1993).
2) Increased deaths from biliary cancer were seen in women 10 years after the Seveso accident, in which the 1976 blowout of a 2,4,5-trichlorophenol production reactor released TCDD over large area near Seveso, Italy, but they were not dose-related (Bertazzi et al, 1989; Schardein, 2000). The relative risk for morbidity among persons in the intermediate-exposure group was 2.8 (Bertazzi et al, 1993).

J) GASTRIC CARCINOMA

1) There is reportedly limited/suggestive evidence of no association between dioxin exposure and stomach, pancreatic, colon and rectal cancers (IOM, 1993).
2) However, a 15 year study of cancer risk in Seveso, after the 1976 blowout of a 2,4,5-trichlorophenol production reactor released TCDD over large area near Seveso, Italy, found a moderate increase in mortality from 'digestive' cancer among women in the zone of highest exposure to dioxin, and, in an area of lower exposure, increased mortality from stomach cancer in women and increased mortality from rectal cancer in men (Bertazzi et al, 1997).
3) Workers exposed to TCDD had an increase in cancer mortality from 'digestive cancer' (Goldfrank, 1998). Increased deaths from stomach cancer (3 versus 0.6 expected) occurred in a group of 74 persons exposed to TCDD in an industrial accident (Thiess et al, 1982).

K) BREAST CARCINOMA

1) An increased incidence of breast cancer was seen in a group of Swedish women who consumed a diet high in fatty fish contaminated with persistent organochlorine compounds from the Baltic Sea, in relation to the general Swedish population and a comparison group from the west coast (Rylander & Hagmar, 1995).

L) THYROID CARCINOMA

1) An increased incidence of thyroid cancer (RR=4.6; n=2 cases) was seen in the youngest population segment 10 years after the Seveso accident, in which the 1976 blowout of a 2,4,5-trichlorophenol production reactor released TCDD over a large area near Seveso, Italy (Pesatori et al, 1993; Schardein, 2000).

3.21.4)

A) CARCINOMA

1) TCDD is a carcinogen in rats, mice and hamsters (EPA, 1994b). It induced hepatocellular carcinomas in female but not male rats (5).
2) TCDD and the furans PCDF and HCDF are also promoters for inducing skin tumors in hairless mice by the dermal route (Hebert et al, 1990).

a) It is the most potent known animal carcinogen and tumor promoter (Bingham et al, 2001; Xu et al, 1992). It is a potent hepatocarcinogen that initiates and promotes cancer (Baxter et al, 2000).

B) CARCINOGENICITY IN MICE

1) In mice, TCDD induces tumors of the thyroid gland, lung, liver, lymphatics, skin, and subcutaneous tissue and induces thymic lymphomas (Huff et al, 1991; ILO, 1998; RTECS , 2001).
2) In mice, TCDD induced tumors of the thyroid gland, liver, and subcutaneous tissue, and induced thymic lymphomas (Huff et al, 1991). Thymic lymphomas were induced in both sexes of (C57BL/6J X C3Hf)F1 (B6C3) and (C57/BL/6J X BALB/c)F1 (B6C) hybrid mice when given in six intraperitoneal doses of 60 mcg/kg TCDD. Hepatocellular adenomas were increased in B6C3 but not B6C mice (Della Porta et al, 1987).
3) In a gavage study, TCDD induced hepatocellular carcinomas in both sexes and follicular-cell thyroid adenomas in female mice (11).
4) TCDD induced fibrosarcomas in the integumentary system of female mice when applied dermally in acetone at a dose of 0.005 mcg, 3 days/week for 104 weeks (11).
5) RESULTS WITH RELATED COMPOUNDS: DICHLOROdibenzo-p-dioxin induced leukemias or lymphomas in male but not female mice (NCI, 1979).

C) CARCINOGENICITY IN RATS

1) In rats, TCDD induced tumors of the liver, lung, oral/nasal cavities, kidneys, adrenal and thyroid glands (Huff et al, 1991; ILO, 1998; RTECS , 2001).
2) TCDD promoted ovarian tumor development in Sprague-Dawley rats after initiation with diethylnitrosamine (Davis et al, 2000).
3) Hepatocellular carcinomas, squamous cell carcinomas of the lung, hard palate, and nasal turbinates developed in rats ingesting 0.1 mcg/kg/day for 2 years. Tumors appeared only in rats manifesting other signs of toxicity, and the NOAEL was 0.001 mcg/kg/day. Hepatocellular carcinomas were sex-specific in female rats only (Kociba et al, 1978).
4) This study was re-evaluated using current criteria for assigning scores to hepatocellular carcinomas in female rats from the original slides. The conclusion was that TCDD is still carcinogenic, but only one-third as potent as previously thought, with a NOAEL of 0.01 mcg/kg/day (Keenan et al, 1991).
5) A 38% incidence of neoplasms was seen in male rats fed TCDD at levels of 1 to 1000 ppb in the diet (VanMiller et al, 1977).
6) In a gavage study, TCDD induced follicular-cell thyroid adenomas in male and neoplastic liver nodules in female Osborne-Mendel rats (11).
7) RESULTS WITH RELATED COMPOUNDS include:

a) A mixture of HEXAchlorodibenzo-p-dioxins induced hepatocellular carcinomas and adenomas in female but not male Osborne-Mendel rats at doses up to 5 mcg/kg/week for 104 weeks by gavage (5).
b) DICHLOROdibenzo-p-dioxin was not carcinogenic in Osborne-Mendel rats (NCI, 1979).

D) CARCINOGENICITY IN HAMSTERS

1) Squamous cell carcinomas developed in Syrian golden hamsters given a total dose of 600 mcg/kg TCDD by the subcutaneous or intraperitoneal route. Hamsters are the species most resistant to the acute effects of TCDD (Huff et al, 1991; Rao et al, 1988).
2) PROMOTING ACTIVITY results include:

a) TCDD is the most potent tumor promoter known; it increases cell turnover and fixes DNA defects (Baxter et al, 2000; Xu et al, 1992).
b) The degree of tumor promotion by TCDD in different strains of mice that differed in their aryl hydrocarbon receptor genotype was not directly related to the level of induction of cytochrome P450 1A. This result indicates that other genetic factors are involved in determining the extent of tumor promotion by TCDD (Beebe et al, 1995).
c) TCDD and dioxin-like compounds 2,3,4,7,8-pentachlorodibenzofuran (PCDF), and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF), were all potent promoters of MNNG-induced squamous cell papillomas in hairless mice via the dermal route (Hebert et al, 1990).
d) 1,2,3,7,8-Pentachlorodibenzo-p-dioxin (PeCDD) was nearly equipotent with TCDD in promoting induction of liver foci in female Sprague-Dawley rats initiated with nitrosamine. 2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) and 3,3',4,4',5-pentachlorobiphenyl (PCB126) were approximately 10% as active as the dioxins (Flodstroem & Ahlborg, 1992).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Liver enzymes, CBC, prothrombin time, INR, serum lipids, and uroporphyrins should be obtained in acute exposure.
B) Electrodiagnostic studies such as EMG and nerve conduction velocity may be useful in detecting subclinical neuropathy.
C) It is difficult to detect dioxins in blood or tissue and there is no correlation between level and symptoms.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Monitor liver enzymes and serum lipids (Hayes, 1982).

B) HEMATOLOGIC

1) Monitor CBC.

C) COAGULATION STUDIES

1) Monitor prothrombin time (International Normalized Ratio) in patients with significant toxicity.

D) SERUM CONCENTRATIONS

1) Serum dioxin concentrations measured in 1987 were similar in veterans with and without Vietnam duty in 1967 to 1968 (4.1 and 4.2 ng/L, respectively) (Baselt, 2000).
2) However, plasma TCDD levels measured in Seveso in 1992-1993, following the 1976 blowout of a 2,4,5-trichlorophenol production reactor released TCDD over large area, showed that those with the highest exposure had the highest levels (mean, 53.2 ppt), and levels decreased with decreasing exposure, with means of 11.0 ppt down to 4.9 ppt for unexposed (Landi et al, 1998).
3) Serum TCDD levels of the highest known occupationally exposed group ranged from <20 pg/g to >148 pg/g (ppt) (Halperin et al, 1995).
4) Serum TCDD levels were as high as 56,000 ppt in persons acutely exposed in the Seveso accident who did not develop chloracne. These are the highest serum levels ever measured, but there were no apparent adverse clinical effects in this group (Mocarelli et al, 1991).
5) Average blood levels of dioxins and dioxin-like substances were similar in Europe and North America; total TEQ (TCDD equivalents) was 42 pg/g (42 ppt) in German subjects and 41 pg TEQ/g in US subjects (Schecter, 1991).
6) Blood levels of 2,3,7,8-TCDD correlated with adipose tissue levels in fasted Vietnam veterans. Although blood analysis was less invasive than a fat biopsy, 300 to 400 mL of blood were needed for the analysis (Kahn et al, 1988).
7) Serum TCDD levels are an accurate 'surrogate' for steady-state levels in human adipose tissue from low-level exposures (Patterson et al, 1988). Serum levels may not be predictive of the severity of clinical effects, however (Mocarelli et al, 1991).
8) PERSISTENT BLOOD LEVELS - Significant serum dioxin levels were measured in a chemist 35 years after exposure. In this single case, the serum level was 18 ppt, compared with a mean level of 5 ppt in the general population (Schecter & Ryan, 1992).

4.1.3)

A) URINARY CONCENTRATIONS

1) 2,4-dichlorophenoxyacetic acid (2,4-D) can be detected in urine (Baselt, 1997). Dioxin is a contaminant of some preparations of 2,4,-D.
2) Monitoring urinary uroporhyrins may be of value after substantial exposure. Uroporphyrin output reached 2.23 mg/24 hours in workers exposed to TCDD who then developed porphyria; excretion of delta aminolevulinic acid increased (Hayes, 1982).
3) Ratios of urinary caffeine metabolites are a measure of induction of cytochrome P-4501A2, a genetically determined response to TCDD exposure (Halperin et al, 1995).
4) An increase in urinary uroporphyrins and coproporphyrins is an early sign of porphyria cutanea tarda (Bleiberg et al, 1964).

4.1.4)

A) OTHER

1) ADIPOSE CONCENTRATIONS

a) TCDD accumulates in fat stores, and is detectable in adipose tissue (Harbison, 1998). However, fat biopsies are not routinely useful. Analysis of Vietnam veterans showed levels from 0 to 13 ppt, which were not different from unexposed controls. Adipose tissue samples from Canada showed random levels of 4 to 130 ppt.
b) Average body burdens in humans from background environmental exposure are 40 to 60 pg TEQ (TCDD equivalents) per gram lipid, including all dioxins, furans, and polychlorinated biphenyls. This is equivalent to approximately 40 to 60 ppt, or 9 ng/kg, from an average daily intake of 3 to 6 pg TEQ/kg/day. Body burdens of dioxins and chlorobenzodifurans increase with age (EPA, 1994b).
c) In a 10-year follow-up of veterans of Operation Ranch Hand, the half-life of TCDD was estimated to be 8.7 years; the half-life was directly related to the amount of body fat, but not with age or relative changes in percent of body fat (Michalek et al, 1996).
d) Median half-life for elimination of TCDD in occupationally exposed persons was estimated to be 7.2 years in a one-compartment, first-order kinetic model (Fleschjanys et al, 1996).
e) Body burdens of dioxins and dioxin-like substances associated with onset of various clinical effects in humans are (EPA, 1994b):

Estimated Body Burden (ng/kg)	Effect
9	"Background" level
14	Decreased testis size
14 to 110	Altered glucose tolerance
45 to 3,000	Chloracne
83	Decreased testosterone
109 to 7,000	Cancer

f) The highest occupational exposures to TCDD measured so far were in nine chemical production workers, who had an average concentration in adipose tissue of 246 ppt, compared with 8.7 ppt in unexposed employees at the same plant (Patterson et al, 1989).
g) Levels of TCDD found in 27 residents of South Vietnam measured in 1989 ranged from 0.3 to 49.6 ppt in adipose tissue. This would have been approximately 20 years after peak exposure to TCDD in Agent Orange. Levels of other dioxin and furan isomers paralleled TCDD in this population (Verger et al, 1994).
h) Cumulative exposure over time is given by the area under the time-concentration curve for dioxin in fat (Bois & Eskenazi, 1994).

2) ELECTROPHYSIOLOGICAL TESTING

a) Electrodiagnostic studies such as EMG and nerve conduction velocity may be useful in detecting subclinical neuropathy.

Methods

1) It is difficult and expensive to detect dioxin in human tissue specimens. The average cost is between $1,500 and $2,500 per sample (Schecter et al, 1994).

1) In one case report, gas chromatography and high-resolution mass spectrometry were used to identify and quantify TCDD and its metabolites in samples of blood serum, adipose tissue, feces, skin, urine, and sweat from the poisoned patient (Sorg et al, 2009).
2) Because levels are very low, a very sensitive and specific method is required. 2,4-dichlorophenol can be detected in plasma and urine using flame-ionization chromatography with on-color methylation (Baselt, 1997).
3) The current analytical techniques involve gas chromatography and mass spectrometry (Raisanen et al, 1981). High resolution gas chromatography with mass spectrometry has a lower detection limit of 0.6 ppt on a lipid-weight basis (Johnson et al, 1992).
4) Cloud-point extraction of serum using Triton X-100 shows promise as a cleaner and easier way to analyze polycyclic aromatic hydrocarbons and polychlorinated dibenzo-p-dioxins (Sirimanne et al, 1996).
5) There is a large margin of error in measuring levels of dioxin less than 100 ppt; error may range from 20 to 50 percent. This concentration range would include almost all biological samples except those from patients with very high acute exposures (Verger et al, 1994).
6) An enzyme-linked immunosorbent assay for TCDD using monoclonal antibodies has a lower detection limit of 0.5 ng (Stanker et al, 1987).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) All patients who are acutely symptomatic should be admitted for observation.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a medical toxicologist for assistance with any acute exposure or if the diagnosis is unclear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients should be observed in a medical facility until free of acute symptoms. Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.

Monitoring

Oral Exposure

6.5.1)

A) SUMMARY

1) DERMAL: Remove contaminated clothing and wash exposed area extremely thoroughly with soap and water. Personnel involved in washing patients should wear gloves and avoid contact with contaminated clothing.
2) OCULAR: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persists after 15 minutes of irrigation, and ophthalmologic examination should be performed.
3) ORAL: Activated charcoal: Most exposures are chronic and routine gastrointestinal decontamination is not indicated. In the unlikely event of acute ingestion, administer activated charcoal if conditions are appropriate.

6.5.2)

A) SUMMARY: Gastric lavage: Consider it in the unlikely case of severe acute ingestions if it can be performed soon after ingestion. Activated charcoal: Most exposures are chronic and routine gastrointestinal decontamination is not indicated. In the unlikely event of acute ingestion, administer activated charcoal if conditions are appropriate.
B) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

C) GASTRIC LAVAGE

1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

2) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

3) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

4) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

5) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

6.5.3)

A) MONITORING OF PATIENT

1) Liver enzymes, CBC, prothrombin time, INR, serum lipids, and uroporphyrins should be obtained in acute exposure.
2) Electrodiagnostic studies such as EMG and nerve conduction velocity may be useful in detecting subclinical neuropathy.
3) It is difficult to detect dioxins in blood or tissue and there is no correlation between level and symptoms.

B) CHLORINE ACNE

1) Chloracne is generally resistant to modes of therapy used for acne vulgaris. Acne surgery and dermabrasion have been the most beneficial in severe cases. Topical retinoic acid 0.05% to 0.3% for up to 10 months may be useful (Plewig, 1971). Tetracyclines may be used to treat secondary pustular follicles.

C) CORTICOSTEROID

1) In acute exposures, it may be beneficial to administer dexamethasone, as this appears to inhibit dioxin-mediated toxicity in animal studies (Taylor et al, 1992).

D) INJURY DUE TO CHEMICAL EXPOSURE

1) VIETNAM REGISTRY: An Agent Orange registry has been established for any Vietnam veteran expressing a concern of exposure to herbicides. Registry includes a thorough history, physical exam, follow-up over several years. Call Agent Orange Helpline toll-free 800-749-8387.

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

B) PERSONNEL PROTECTION

1) Personnel involved in washing patients should wear gloves and avoid contact with contaminated clothing.

6.9.2)

A) CHLORINE ACNE

1) Chloracne is generally resistant to modes of therapy used for acne vulgaris. Tetracyclines, topically or orally, have proven useful in some cases. Acne surgery and dermabrasion have been beneficial in severe cases. Topical retinoic acid 0.05% to 0.3% for up to 10 months may be useful (Plewig, 1971).

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Abstracts

Case Reports

1) Three men involved in the synthesis of TCDD developed chloracne, hyperpigmentation, and hypercholesterolemia despite observing appropriate precautions. Two developed hirsutism, anorexia, headaches, and fatigue 2 years after the episode (Oliver, 1975). These are the only known cases of significant exposure to pure TCDD.

1) A 6-year-old girl playing in a Missouri horse arena sprayed with TCDD-contaminated motor oil developed self-limited epistaxis, severe hemorrhagic cystitis, and GI complaints. Samples taken from the arena soil contained 31.8 to 33 ppm of TCDD (Beale et al, 1977).

Range Of Toxicity

Summary

Minimum Lethal Exposure

1) One review article by Reggiani (1978) reports a minimum lethal dose of 1 mcg/kg (Reggiani, 1978; Schardein, 2000).
2) It is estimated that human lethal doses are greater than 100 mcg/kg (Neal, 1983).

Maximum Tolerated Exposure

1) DERMAL

a) Assuming daily exposure, it appears that 10 to 30 ppm in oil and 100 to 3,000 ppm in soil-water mixtures are necessary to produce objective effects. Soil concentrations likely to produce chloracne with daily contact probably exceed 100 ppm (Dunagin, 1984).
b) The lowest published toxic dose for a human (dermal route) is 107 mcg/kg (Lewis, 2000; RTECS , 2002).

2) INHALATION

a) Dioxin has a low vapor pressure (1.7 x 10(-6) mmHg). Inhalation of 70 ng/human/day is the FDA-suggested "no effect" level. If the level in dirt/dust is 1 ppb, the amount inhaled has been calculated as 1.4 pg/day.

3) AIRBORNE

a) SEVESO, ITALY INCIDENT - A plant producing trichlorophenol in Seveso, Italy, inadvertently overheated, creating a cloud of dioxin (TCDD) containing 650 to 1700 grams (35,000 ppt). Children and adults directly exposed to airborne dust complained of nausea, skin redness, and swelling. Others developed chloracne, which rapidly and spontaneously healed, subclinical peripheral neurological impairment, and liver enzyme abnormalities. The highest average soil levels were 584 ppb (Reggiani, 1978).

4) ORAL -

a) Cumulative oral doses of 100 mcg/kg are estimated as the minimum toxic dose. The World Health Organization recommended in 1998 that the tolerable daily intake of TCDD not exceed 4 picograms/kg (Birnbaum & Slezak, 1999).

5) SOIL LEVELS -

a) Soil levels of 1 ppb are estimated to increase the risk of developing cancer by 1 in 1 million (MMWR, 1984).
b) Soil concentrations likely to produce chloracne with daily contact probably exceed 100 ppm (Dunagin, 1984).
c) A 6-year-old girl playing in a Missouri horse arena sprayed with dioxin (TCDD)-contaminated motor oil developed self-limited epistaxis, severe hemorrhagic cystitis, and gastrointestinal complaints. Samples taken from the soil contained 31.8 to 33 ppm of dioxin (TCDD) (Beale et al, 1977).

1) Hen pheasants injected with graded single doses of dioxin (TCDD) (6.25, 25 or 100 mcg/kg) had delayed-onset body weight loss and mortality, classic signs of the wasting syndrome (Nosek et al, 1992).

a) The lowest single dose of dioxin (TCDD) to produce this effect was 25 mcg/kg.
b) When hen pheasants were treated weekly with lower doses of dioxin (TCDD) (0.01 to 1.0 mcg/kg/wk) for 10 weeks, signs of the wasting syndrome and mortality were also produced.
c) The lowest cumulative dioxin (TCDD) dose required to produce the wasting syndrome, using a weekly dosing regimen, was 10 mcg/kg. At this dosing regimen, egg production by hens treated with a cumulative dioxin (TCDD) dose of 10 mcg/kg was reduced, as was egg hatchability.

2) RATS: The maximum tolerated dose of TCDD in rats in a 91-day subchronic gavage study was 0.1 pg/kg/day (Ivens et al, 1993).
3) RATS: The maximum tolerated dose of TCDD in rats was 0.01 mcg/kg/day when given 5 days/week for 13 weeks (Kociba et al, 1976).
4) TCDD and two dioxin-like compounds, 2,3,4,7,8-pentachlorodibenzofuran (PCDF), and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF), were evaluated for relative dermal toxicity in 20-week subchronic skin painting studies in hairless mice (Hebert et al, 1990).

a) Based on dermatotoxic effects and changes in body and organ weights, the last two compounds were relatively more toxic than their acute Toxicity Equivalency Factor (TEF) values would indicate.
b) TEF values may underestimate the risk from repeated low-dose exposures, at least for these compounds.

1) Where TCDD has been assigned a Toxicity Equivalency Factor (TEF) of 1.0 (on a scale of 0 to 1.0, with 1.0 being the most toxic), the other chlorinated dibenzodioxins and chlorinated dibenzofurans have TEFs ranging from 0 to 0.5 (Freeman, 1998).
2) TCDD is the most toxic of all the known dioxins. Of the 210 possible positional congeners, only 7 chlorinated dibenzodioxins and 10 chlorinated dibenzofurans are believed to have TCDD-like activity. These all have chlorine in the 2,3,7 and 8 positions (EPA, 1994a; EPA, 1994b; Freeman, 1998).
3) The EPA's Exposure Estimation for Dioxin-Like Compounds mainly deals with chlorinated dibenzodioxins and, by extension, chlorinated dibenzofurans and other dioxin-like compounds. Analogous brominated dioxins and furans, and certain polychlorinated biphenyls, are known to have dioxin-like toxicity but have not yet been assigned TEFs (EPA, 1994a).
4) Only 11 of the 209 possible polychlorinated biphenyl congeners are thought to have dioxin-like activity. These have at least four chlorine substituents (EPA, 1994a).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) INTENTIONAL POISONING

a) In one poisoned patient, TCDD concentrations in blood serum and fat were 108,000 picograms (pg)/g lipid weight (approximately 50,000-fold higher than in general population) and 107,000 pg/g lipid weight, respectively. These concentrations were monitored for over 3 years. In the lipids, TCDD concentrations were 66,000 pg/g and 38,000 pg/g, 11 months and 23 months after the poisoning, respectively. TCD burden, 11 months and 23 months after the poisoning, was 990 mcg and 740 mcg, respectively. This indicated a loss of 250 mcg of TCDD in 12 months (Sorg et al, 2009).

2) OCCUPATIONAL

a) Heavily exposed Vietnam veterans had blood levels of 2,3,7,8-TCDD exceeding 15 pg/gram 15 to 20 years after exposure (Kahn et al, 1988).
b) Median TCDD levels of 8 pg/gram plasma lipid (range, 2 to 13) were detected among 11 Swedish men who ate fish almost daily (Svensson et al, 1991). Lower levels were reported among moderate-intake and nonconsumer groups. Clinical correlations were not studied.

Workplace Standards

1) Not Listed

1) Listed as: 2,3,7,8-Tetrachloro-dibenzo-p-dioxin
2) REL:

a) TWA:
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Ca) NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
e) Skin Designation: Not Listed
f) Note(s): See Appendix A

3) IDLH: Not Listed

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 1 ; Listed as: 2,3,7,8-Tetrachlorodibenzo-para-dioxin

a) 1 : The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.

4) NIOSH (National Institute for Occupational Safety and Health, 2007): Ca ; Listed as: 2,3,7,8-Tetrachloro-dibenzo-p-dioxin

a) Ca : NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).

5) MAK (DFG, 2002): Category 4 ; Listed as: 2,3,7,8-Tetrachlorodibenzo-p-dioxin

a) Category 4 : Substances with carcinogenic potential for which genotoxicity plays no or at most a minor part. No significant contribution to human cancer risk is expected provided the MAK value is observed. The classification is supported especially by evidence that increases in cellular proliferation or changes in cellular differentiation are important in the mode of action. To characterize the cancer risk, the manifold mechanisms contributing to carcinogenesis and their characteristic dose-time-response relationships are taken into consideration.

6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): K ; Listed as: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), Dioxin

a) K : KNOWN = Known to be a human carcinogen

1) Not Listed

Toxicity Information

7.7.1)

A) References: Bingham et al, 2001 HSDB, 2002 Lewis, 2000 NTP, 2001;) Pohjanvirta et al, 1993 RTECS, 2002 Verschueren, 2001

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 120 mcg/kg

2) LD50- (ORAL)MOUSE:

a) 114 mcg/kg -- convulsions, cardiac changes, mydriasis

3) LD50- (INTRAPERITONEAL)RAT:

a) 24,600 ng/kg

4) LD50- (ORAL)RAT:

a) 20 mcg/kg
b) Male, 22.0 mcg/kg (HSDB, 2002)
c) Sprague-Dawley, 43 mcg/kg (Bingham et al, 2001)
d) Female, 45.0 mcg/kg (HSDB, 2002)
e) >7200 mcg/kg -- H/W strain (Pohjanvirta et al, 1993)
f) Female, 9.8 mcg/kg -- L-E strain (Pohjanvirta et al, 1993)
g) Male, 17.7 mcg/kg -- L-E strain (Pohjanvirta et al, 1993)

Pharmacology Toxicology

Toxicologic Mechanism

1) Toxic dioxins and dioxin-like compounds consist of two or more aromatic rings in a planar configuration, with four lateral halogen atoms arranged in a 3- x 10-Angstrom rectangular box. Additional chlorine atoms may be present, and tend to decrease toxicity, presumably by increasing molecular thickness and interfering with binding to the receptor.

1) This results in the induction of pleiotropic expression of specific genes, including several cytochrome P450 genes, notably the CYP1A1 gene for cytochrome P-4501A1 (Baxter et al, 2000; EPA, 1994b). This ultimately affects intracellular calcium levels, cytokine expression and estrogen expression; these secondary effects, in turn, lead to other physiological changes (Baxter et al, 2000; EPA, 1994b).
2) Cytochrome P-4501A2 is also induced in rats, but to a lesser extent (Tritscher et al, 1992). In experimental animals, toxicity is related to the induction of cytochromes P-448 and P-450 (McKinney & McConnell, 1982).

1) For example, the mouse strain C56BL/6J is more sensitive to the acute lethal effects of TCDD, and to the induction of cytochrome P-450, than strain DBA/2J (Chapman & Schiller, 1985; Poland & Glover, 1975).

1) TCDD can induce superoxide formation in mouse peritoneal lavage cells (mainly macrophages). This induction is at least partially dependent on the aryl hydrocarbon receptor-TCDD complex (Alsharif et al, 1994).
2) Dioxin appears to inhibit hepatic selenium-dependent, but not selenium-independent, glutathione peroxidase in rats. Optimum dietary selenium seems to provide partial protection from the toxic effects of dioxin in rats (Hassan et al, 1985).

Physicochemical

Physical Characteristics

Molecular Weight

Animal Toxicology

Clinical Effects

11.1.5)

A) CHRONIC EXPOSURE - Horses exposed chronically to wood shavings contaminated with dioxins exhibited alopecia, a crusty, scaly dermatitis, weight loss, intestinal colic, pitting edema, polypnea, moist lung sounds, nasal discharge, and high heart rate. A liver biopsy revealed hepatotoxicosis including porphyria and edematous effects. Other noted effects were an immunotoxicity, respiratory distress, and hoof problems (Kerkvliet et al, 1992).

Other

1) Schilling & Stehr-Green (1987) studied family pets to determine if the pets could serve as sentinels of human health risks associated with waste oils contaminated with TCDD that were sprayed for dust control. No correlation could be identified based on confirmed pet illnesses.
2) Factors responsible for large differences in species sensitivity are not understood (Hatch & Stein, 1986).

References

General Bibliography

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DIOXINS

Classification | Detailed evidence-based information

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General Bibliography