1. Exposure Data

1.1. Identification of the agents

From NTP (2006a, b, c)

1.1.1. 2,3,7,8-Tetrachlorodibenzo-para-dioxin (2,3,7,8-TCDD, TCDD)

• Chem. Abstr. Serv. Reg. No.: 1746-01-6
• Chem. Abstr. Serv. Name: 2,3,7,8-Tetrachlorodibenzo[b,e][1,4]dioxin
• Synonyms: 2,3,7,8-TCDD; TCDD; dioxin; tetradioxin

• C₁₂H₄Cl₄O₂
• Relative molecular mass: 321.98
• Description: Colourless to white crystalline solid
• Solubility: Insoluble in water; slightly soluble in n-octanol and methanol; and soluble in other organic solvents (e.g. dichlorobenzene, chlorobenzene, benzene, chloroform, and acetone)
• Octanol/water partition coefficient: log K_ow, 6.80

1.1.2. 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PeCDF)

• Chem. Abstr. Serv. Reg. No.: 57117-31-4
• Chem. Abstr. Serv. Name: 2,3,4,7,8-Pentachlorodibenzofuran
• Synonym: 2,3,4,7,8-PeCDF; 2,3,4,7,8-penta-CDF

• C₁₂H₃Cl₅O
• Relative molecular mass: 340.42
• Description: Solid with a melting point of 195–196 °C (NTP Chemical Repository Information). It is stable under normal laboratory conditions.
• Solubility in water: 2.36 × 10⁻⁴ mg/L at 22.7 °C
• Octanol/water partition coefficient: log K_ow, 6.92

1.1.3. 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126)

• Chem. Abstr. Serv. Reg. No.: 57465-28-8
• Chem. Abstr. Serv. Name: 3,3′,4,4′,5-Pentachlorobiphenyl
• Synonym: PCB 126

• C₁₂H₅Cl₅
• Relative molecular mass: 326.42
• Description: Solid with a melting point of 160–161 °C.
• Solubility in water: 1.03 × 10⁻³ mg/L at 25 °C
• Octanol/water partition coefficient: log K_ow, 6.89

2. Cancer in Humans

Human exposures related to occupation or accidents have led to tissue concentrations of 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) that are 10–100-fold higher than average background levels in the 1980s. The highest exposures occurred in industrial cohorts of workers producing phenoxy herbicides and chlorophenols, while exposure to professional sprayers of these compounds was considerably lower. It has been shown that TCDD levels in professional applicators increase considerably above background only after several years of spraying of TCDD-contaminated chemicals. For example, in the most heavily exposed applicators of 2,4,5-T in New Zealand, who applied this chemical for at least 180 months, the estimated mean serum concentration of TCDD at the time of blood drawing was 53 ng/kg (Smith et al., 1992). Occasional spraying is unlikely to lead to any measurable increase in TCDD level.

The evaluation of the evidence of carcinogenicity of TCDD was based on studies with direct measurements of TCDD and studies involving heavy exposure to herbicides likely to be contaminated with TCDD. There are numerous studies that assessed dioxins, furans and polychlorobiphenyls (PCBs) in workers, but these are not systematically reviewed here. These studies indicate that the highest exposure occurs in industrial settings producing 2,4,5-T. There are also numerous studies in workers evaluating a wide range of health effects. Table 2.1 (available at http://monographs.iarc.fr/ENG/Monographs/vol100F/100F-22-Table2.1.pdf) shows estimated exposures to TCDD in industrial workers, in workers handling and spraying 2,4,5-T and in the population in Seveso, Italy. Average exposures in industrial workers are the highest. The effects of TCDD and those of the products in which it was found cannot be separated in most of the epidemiological studies; however, the focus here is on the contaminant. The most important studies for the evaluation of the carcinogenicity of TCDD are cohort studies of herbicide producers, one each in the United States (Fingerhut et al., 1991; Steenland et al., 1999, 2001), the Netherlands (Bueno de Mesquita et al., 1993; Hooiveld et al., 1998; Boers et al. 2010), two in Germany (Manz et al., 1991; Ott et al., 1993; Flesch-Janys et al., 1995, 1998; Becher et al., 1996), and one cohort of residents in a contaminated area from Seveso, Italy (Bertazzi et al., 2001; Pesatori et al., 2009). These studies involve the highest exposures to TCDD among all epidemiological studies, although the exposures at Seveso were lower and the follow-up was shorter than those in the industrial settings. In addition, the multicountry cohort study from IARC (Saracci et al., 1991; Kogevinas et al., 1995, 1997) is of special interest because it includes three of four high-exposure cohorts and other industrial cohorts, many of them not reported in separate publications, as well as information on professional applicators. Most of the industrial cohort studies include analyses of subcohorts considered to have the highest exposure and/or longest latency. These cohorts and their respective high-exposure subcohorts are the focus of this evaluation. In reporting the findings, preference has been given to the most updated follow-up, unless earlier publications presented evidence not included in a later publication, e.g. results by exposure classifications of interest. Results are presented in Table 2.2 (available at http://monographs.iarc.fr/ENG/Monographs/vol100F/100F-22-Table2.2.pdf), Table 2.3 (available at http://monographs.iarc.fr/ENG/Monographs/vol100F/100F-22-Table2.3.pdf), Table 2.4 (available at http://monographs.iarc.fr/ENG/Monographs/vol100F/100F-22-Table2.4.pdf), and Table 2.5 (available at http://monographs.iarc.fr/ENG/Monographs/vol100F/100F-22-Table2.5.pdf). Additional studies of herbicide applicators, both cohort and case–control studies, which have considerably lower exposures to TCDD, are not considered critical for the evaluation and are not reported in the tables. Among the studies not included, there are several that have been widely quoted and that have been important in responding to concerns in the community and in raising public awareness regarding potential effects of dioxin exposure, such as Ketchum & Aktar (1996), Ketchum et al. (1999), and Hardell & Sandström (1979).

3. Cancer in Experimental Animals

3.1 2,3,7,8-Tetrachlorodibenzo-para-dioxin

Carcinogenicity studies with several strains of rats, mice and Syrian hamsters treated with 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) via the oral route (gavage or diet), by intra-peritoneal injection, or by skin application have been reviewed in IARC Monograph Volume 69 (IARC, 1997). At the time, the review of the available data led to the conclusion that there is sufficient evidence in experimental animals for the carcinogenicity of TCDD. The present Monograph also evaluates relevant carcinogenicity studies in TCDD-treated experimental animals that were published since 1997. The results of adequately conducted carcinogenicity studies are summarized below and in Table 3.1 and Table 3.2.

Table 3.1

Carcinogenicity studies in mice exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD).

Table 3.2

Carcinogenicity studies in rats and hamsters exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD).

TCDD was tested for carcinogenicity by oral administration (gavage or dose feed) in four studies in mice and six studies in rats, by skin (topical) application in two studies in mice, by intraperitoneal injection in one study in mice, one study in rats and one study in hamsters and by subcutaneous injection in one study in hamsters. TCDD produced tumours in both sexes of mice and rats, and in multiple organs and tissues.

Oral administration of TCDD caused increased incidences of thyroid follicular adenomas and hepatocellular adenomas and carcinomas in male and female mice, of alveolar/bronchiolar adenomas and carcinomas in male mice, and of histiocytic lymphomas and subcutaneous fibrosarcomas in female mice. In rats, it caused increased incidences of hepatocellular adenomas in males and females, cholangiocarcinomas and hepatocellular carcinomas in females, lung cystic keratinizing epitheliomas and squamous-cell carcinomas in females, adrenal gland (cortex) adenomas and squamous-cell carcinomas of the hard palate/nasal turbinates in males and females, tongue squamous-cell carcinomas and thyroid follicular adenomas and carcinomas combined in males, subcutaneous fibromas in males and subcutaneous fibrosarcomas in females, and pituitary adenomas, uterine and oral mucosa (gingival) squamous-cell carcinomas and pancreatic adenomas and carcinomas combined in females (Van Miller et al., 1977; Kociba et al., 1978; Tóth et al., 1979, NTP, 1982a, 2006a; Della Porta et al., 1987; Goodman & Sauer, 1992; Hays et al., 1997, Yoshizawa et al., 2005). Skin application or gavage caused benign and malignant tumours of the skin in female mice including transgenic mice (NTP, 1982b; Wyde et al., 2004). Hamsters that received TCDD by intraperitoneal or subcutaneous injection developed squamous-cell carcinomas of the facial skin (Rao et al., 1988). Intraperitoneal injection caused increased incidence of hepatocellular adenomas and carcinomas in female mice and of lymphomas in male and female mice (Della Porta et al., 1987).

Several studies in mice showed that administration of TCDD with known carcinogens enhanced the incidence of skin papillomas, lung adenomas, liver adenomas and hepatoblastomas. In female rats, TCDD co-administered with various nitrosamines enhanced the incidence of focal hepatic lesions. In one study, TCDD enhanced the incidence of lung carcinomas in ovariectomized female rats following administration of N-nitrosodiethylamine (NDEA) (IARC, 1997). In two more recent studies in female rats, TCDD given orally or subcutaneously enhanced the carcinogenicity of previously administered NDEA (Davis et al., 2000; Viluksela et al., 2000). In another study, the oral administration of TCDD to pregnant rats increased 7,12-dimethylbenz[a]anthracene-induced mammary-gland tumours in offspring (Brown et al., 1998; see Table 3.3).

Table 3.3

Studies on 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) administered to rats, in combination with known carcinogens or modifying factors.

3.2. Dioxin-like compounds

3.2.1. 2,3,4,7,8-Pentachlorodibenzofuran

Oral administration of 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) resulted in significant dose-dependent trends for increased incidence of cholangiocarcinomas and hepatocellular adenomas (Walker et al., 2005; NTP, 2006b). (see Table 3.4)

Table 3.4

Carcinogenicity and initiation-promotion studies in experimental animals exposed to 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) and 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126).

Skin application of PeCDF after a single dose of N-methyl-N′-nitro-N-nitrosoguanidine resulted in an increased incidence of skin papillomas in mice (Hébert et al., 1990). Subcutaneous injections of PeCDF after oral treatment with NDEA resulted in an increased multiplicity of hepatocellular carcinomas and liver hyperplastic nodules in male rats (Nishizumi & Masuda, 1986). Subcutaneous injections of PeCDF after a single intraperitoneal injection of NDEA increased the number of focal hepatic lesions in female rats (Waern et al., 1991).

3.2.2. 3,3′,4,4′,5-Pentachlorobiphenyl

Oral administration of 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) resulted in significantly increased incidence of hepatocellular adenomas, cholangiocarcinomas, lung cystic keratinizing epitheliomas, and oral mucosa (gingiva) squamous-cell carcinomas in female rats (Walker et al., 2005; NTP, 2006c).

4. Other Relevant Data

4.3. Dioxin-like compounds

As noted above, the carcinogenicity of TCDD is tied to a sustained, pleiotropic response following exposure to dioxin. The 17 laterally-substituted (2,3,7,8-substituted) polychlorinated dibenzodioxins (PCDD-Ls), the coplanar polychlorinated biphenyls (CP-PCBs) and the 17 laterally-substituted polychlorinated dibenzofurans (PCDF-Ls) are all structurally and toxicologically inter-related halogenated aromatic hydrocarbons referred to as dioxin-like compounds (DLCs). They potentially induce pleiotropic responses in cells very similar to those induced by TCDD (IARC, 1978, 1987, 1997; Vezina et al., 2004) as they are all able to bind to the AhR. Binding affinity is different among DLCs, with some of them having so little binding affinity that there is almost no information on their biological impact. We focus here on the 28 DLCs (DLC-28) listed in Table 4.1 that produce a TCDD-like response in human cell lines (Endo et al., 2003), in animal and primary human cells, and in animal and human tissue (Vezina et al., 2004; Silkworth et al., 2005; Kopec et al., 2008; N’Jai et al., 2008).

Table 4.1

Toxicity Equivalence Factors (TEFs) and half-lives of the dioxin-like compounds.

DLCs co-occur in virtually every environmental compartment where they are found, and assessment of their potential effect on human risk can be complicated. Public health authorities (in particular WHO expert panels) have developed the toxicity equivalence factor (TEF) methodology for measuring the potency of DLCs, with TCDD as the index chemical. Exposures are calculated as a simple weighted sum of the individual amounts multiplied by their individual TEFs to yield the equivalent dose in units of TCDD exposure. Only the compounds of the DLC-28 series have TEF values > 0 (Table 4.1), all of the remaining congeners have TEF = 0.

WHO recently evaluated TEFs (Van den Berg et al., 2006) thus reviewing much of the literature on DLCs (Haws et al., 2006), namely 189 studies with over 1000 targets used for analysis. For every compound, there is at least one in vitro study showing AhR binding and one showing 7-ethoxyresorufin-O-dethylase activity, which is associated with an increase in CYP1A1 activity. Congeners 1,2,3,7,8-PeCDD, 2,3,7,8-TCDF, 2,3,4,7,8-PeCDF, and PCB-77, -126, and -169 have a very broad spectrum of information both in animal and in human cells, demonstrating activity consistent with the mechanisms described earlier. In addition, for PCB-81 there are nine studies in human cell lines showing the same alterations in gene expression and enzyme activity as reported for TCDD.

Congeners 1,2,3,7,8-pentaCDD, 1,2,3,4,6,7,8-heptaCDD, a mixture of 1,2,3,6,7,8- and 1,2,3,7,8,9-hexaCDD, and a mixture of PCDDs have been studied in two-stage experimental models (IARC, 1978) and shown to enhance the carcinogenic potential of known carcinogens just like TCDD. There are some human studies on the compounds in the DLC-28 series, but they have either poor exposure characterization or also contain TCDD, making it difficult to interpret their individual effects (IARC, 1978).

While the carcinogenicity of TCDD has been clearly established in rodents, for the remaining compounds in the DLC-28 series bioassays on two-year chronic exposure are lacking. A two-year chronic study on 2,3,4,7,8-PeCDF in rodents (NTP, 2006b) demonstrated tumour effects consistent with those seen for TCDD (hepatocellular adenomas, cholangiocarcinomas, gingival squamous cell carcinomas, and an equivocal finding of lung cystic keratonizing epitheliomas). When compared for potency, the result from this study agreed with the TEF concept (Walker et al., 2005). 2,3,4,7,8-PeCDF and 1,2,3,4,7,8-HxCDF were also enhanced tumorigenesis in two-stage studies of cancer (IARC, 1997). Follow-up of populations in Taiwan, China (Tsai et al., 2007) and Japan (Onozuka et al., 2009) accidentally exposed to rice-oil containing PCDFs and PCBs, shows a significantly increased risk of mortality from chronic liver disease in men and a non-significant increase from liver cancer in men and women in Taiwan, China while in Japan all cancer mortality, and liver and lung cancer-mortalities were increased in men.

The carcinogenicity of mixtures of PCBs in rodents has also been clearly established through studies of various Aroclors (IARC, 1978; Mayes et al., 1998; NTP, 2006c) yielding predominantly liver cancers (Cogliano, 1998). Two-year chronic exposure studies done by the US National Toxicology Program (NTP) on PCB 126 (NTP, 2006d) and PCB 118 (NTP, 2009), demonstrated tumour effects consistent with those seen for TCDD (hepatocellular adenomas, cholangiocarcinomas, gingival squamous cell carcinomas, and lung cystic keratonizing epitheliomas). Moreover, when equivalent TCDD doses where applied with the current TEF, a carcinogenic response equivalent to that predicted for TCDD from the NTP study (Walker et al., 2005) was observed.

The set of DLC-28 (IARC, 1978, 1997; Milbrath et al., 2009) have a long half-life similar to that of TCDD (estimated at 7.2 years in the human body) (Table 4.1). Many congeners have similar or longer half-lives (1,2,3,7,8-PeCDD, 1,2,3,4,7,8- and 1,2,3,6,7,8-HxCDD, 1,2,3,6,7,8- and 1.2.3.7.8.9-HxCDF, and PCBs 169, 114, 123, 156, 167 and 189) while most of the remaining half-lives are in excess of 1.4 years. Several authors report the presence of these compounds in human blood in the general population (Costopoulou et al., 2006; Scott et al., 2008; Zubero et al., 2009) indicating a sustained, long-term exposure that, when coupled with the analyses for common pleiotropic response, argues in favour of the notion that all of the DLC-28s have the same carcinogenic potential in humans.

Experimental data on mechanism of carcinogenesis induced by DLC-28 are available for 2,3,4,7,8-PeCDF and PCB 126, in particular (Table 4.2), Both have been shown to bind to the AhR in humans and animals (IARC, 1978; Safe, 2001), to translocate into the nucleus and activate numerous metabolic enzymes in vitro (human and non-human cell lines) and in vivo in experimental animals (IARC, 1997; Safe, 2001; Vezina et al., 2004; Haws et al., 2006), to trigger changes in growth factors and signalling pathways related to cellular replication in rodents (Hemming et al., 1995; Vondrácek et al., 2005; N’Jai et al., 2008). 2,3,4,7,8-PeCDF potential effect on cell replication is suggested in the NTP study (Walker et al., 2007), and promotion in skin, liver and lung tissues is reported in initiation-promotion studies (Hébert et al., 1990; Anderson et al., 1991; Waern et al., 1991). PCB 126 acts as a promoter of liver cancer in initiation-promotion studies (Hemming et al., 1995; Haag-Grönlund et al., 1998) with measured increases in cell-replication rate in the populations of initiated cells (Vondrácek et al., 2005). PCB 126 and 2,3,4,7,8-PeCDF induce oxidative stress, the latter in a dose-dependent manner in brain and liver of rats (Hassoun et al., 2002; Hennig et al., 2002). These two compounds are carcinogenic in mixtures with TCDD (IARC, 1978; Hassoun et al., 2001; NTP, 2006d) and by themselves in the NTP chronic bioassays in rats, where they increase hepatocellular adenomas, cholangiocarcinomas, gingival squamous-cell carcinomas, and, possibly, lung cystic keratonizing epitheliomas (NTP, 2006b, c, d).

Table 4.2

Experimental evidence on the mechanisms of carcinogenesis for TCDD and the dioxin-like compounds 2,3,4,7,8-PeCDF and PCB 126 (positive, non-determined, and indirect).

5. Evaluation

There is sufficient evidence in humans for the carcinogenicity of 2,3,7,8-tetrachlorodibenzo-para-dioxin. The strongest evidence in humans for the carcinogenicity of 2,3,7,8-tetrachlorodibenzo-para-dioxin is for all cancers combined.

Also, a positive association has been observed between exposure to 2,3,7,8-tetrachlorodibenzo-para-dioxin and soft-tissue sarcoma, non-Hodgkin lymphoma and cancer of the lung.

There is sufficient evidence in experimental animals for the carcinogenicity of 2,3,7,8-tetrachlorodibenzo-para-dioxin.

There is sufficient evidence in experimental animals for the carcinogenicity of 2,3,4,7,8-pentachlorodibenzofuran.

There is sufficient evidence in experimental animals for the carcinogenicity of 3,3′,4,4′,5-pentachlorobiphenyl.

There is strong evidence to support a receptor-mediated mechanism that operates in humans for carcinogenesis associated with 2,3,7,8-tetrachlorodibenzo-para-dioxin, where the primary mechanism is the promotion of tumour development through modification of cell replication and apoptosis, with a secondary mechanism related to increases of oxidative stress causing DNA damage. The conservation of the aryl hydrocarbon receptor and the related signalling pathways and responses across species, including humans, add additional strength to the notion that this mechanism is active in humans.

2,3,7,8-Tetrachlorodibenzo-para-dioxin is carcinogenic to humans (Group 1).

2,3,4,7,8-Pentachlorodibenzofuran is carcinogenic to humans (Group 1).

3,3′,4,4′,5-Pentachlorobiphenyl is carcinogenic to humans (Group 1).

In making the second and third overall evaluations, the Working Group considered the following mechanistic arguments:

There is strong evidence to support a receptor-mediated mechanism for 2,3,4,7,8-pentachlorodibenzofuran- and 3,3′,4,4′,5-pentachlorobiphenyl-associated carcinogenesis in humans based upon evidence of carcinogenicity in experimental animals and upon extensive evidence showing activity identical to 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) for every step of the mechanism described for TCDD-associated carcinogenesis in humans including receptor binding, gene expression, protein-activity changes, cellular replication, oxidative stress, promotion in initiation-promotion studies and complete carcinogenesis in laboratory animals.

References

• Anderson LM, Beebe LE, Fox SD, et al. Promotion of mouse lung tumors by bioaccumulated polychlorinated aromatic hydrocarbons. Exp Lung Res. 1991;17:455–471. [PubMed: 1904809]
• ATSDR (1998). Toxicological Profile for Chlorinated Dibenzo-p-dioxins. Atlanta, GA, pp. 21.
• Aylward LL, Bodner KM, Collins JJ, et al. TCDD exposure estimation for workers at a New Zealand 2,4,5-T manufacturing facility based on serum sampling data. J Expo Sci Environ Epidemiol. 2010;20:417–426. [PubMed: 19491942]
• Aylward LL, Hays SM. Temporal trends in human TCDD body burden: Decreases over three decades and implications for exposure levels. J Expo Anal Environ Epidemiol. 2002;12:319–328. [PubMed: 12198580] [CrossRef]
• Baars AJ, Bakker MI, Baumann RA, et al. Dioxins, dioxin-like PCBs and non-dioxin-like PCBs in foodstuffs: occurrence and dietary intake in The Netherlands. Toxicol Lett. 2004;151:51–61. [PubMed: 15177640] [CrossRef]
• Baccarelli A, Mocarelli P, Patterson DG Jr, et al. Immunologic effects of dioxin: new results from Seveso and comparison with other studies. Environ Health Perspect. 2002;110:1169–1173. [PMC free article: PMC1241102] [PubMed: 12460794]
• Barrett JC. Mechanisms for species differences in receptor-mediated carcinogenesis. Mutat Res. 1995;333:189–202. [PubMed: 8538627]
• Bates MN, Buckland SJ, Garrett N, et al. Persistent organochlorines in the serum of the non-occupationally exposed New Zealand population. Chemosphere. 2004;54:1431–1443. [PubMed: 14659945] [CrossRef]
• Becher H, Flesch-Janys D, Kauppinen T, et al. Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins. Cancer Causes Control. 1996;7:312–321. [PubMed: 8734824] [CrossRef]
• Becher H, Steindorf K, Flesch-Janys D. Quantitative cancer risk assessment for dioxins using an occupational cohort. Environ Health Perspect. 1998;106 Suppl 2):663–670. [PMC free article: PMC1533398] [PubMed: 9599714] [CrossRef]
• Beebe LE, Fornwald LW, Diwan BA, et al. Promotion of N-nitrosodiethylamine-initiated hepatocellular tumors and hepatoblastomas by 2,3,7,8-tetrachlorodibenzo-p-dioxin or Aroclor 1254 in C57BL/6, DBA/2, and B6D2F1 mice. Cancer Res. 1995;55:4875–4880. [PubMed: 7585523]
• Berkers JA, Hassing I, Spenkelink B, et al. Interactive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and retinoids on proliferation and differentiation in cultured human keratinocytes: quantification of cross-linked envelope formation. Arch Toxicol. 1995;69:368–378. [PubMed: 7495374]
• Bertazzi PA, Consonni D, Bachetti S, et al. Health effects of dioxin exposure: a 20-year mortality study. Am J Epidemiol. 2001;153:1031–1044. [PubMed: 11390319] [CrossRef]
• Biegel L, Safe S. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on cell growth and the secretion of the estrogen-induced 34-, 52- and 160-kDa proteins in human breast cancer cells. J Steroid Biochem Mol Biol. 1990;37:725–732. [PubMed: 2278856]
• Boers D, Portengen L, Bueno-de-Mesquita HB, et al. Cause-specific mortality of Dutch chlorophenoxy herbicide manufacturing workers. Occup Environ Med. 2010;67:24–31. [PubMed: 19736176] [CrossRef]
• Bond GG, McLaren EA, Lipps TE, Cook RR. Update of mortality among chemical workers with potential exposure to the higher chlorinated dioxins. J Occup Med. 1989;31:121–123. [PubMed: 2709162]
• Brown NM, Manzolillo PA, Zhang J-X, et al. Prenatal TCDD and predisposition to mammary cancer in the rat. Carcinogenesis. 1998;19:1623–1629. [PubMed: 9771934] [CrossRef]
• Bueno de Mesquita HB, Doornbos G, Van der Kuip DAM, et al. Occupational exposure to phenoxy herbicides and chlorophenols and cancer mortality in The Netherlands. Am J Ind Med. 1993;23:289–300. [PubMed: 8427257] [CrossRef]
• Burns CJ, Collins JJ, Budinsky RA, et al. Factors related to dioxin and furan body levels among Michigan workers. Environ Res. 2008;106:250–256. [PubMed: 18054905] [CrossRef]
• Charnley G, Doull J. Human exposure to dioxins from food, 1999–2002. Food Chem Toxicol. 2005;43:671–679. [PubMed: 15778006] [CrossRef]
• Charnley G, Kimbrough RD. Overview of exposure, toxicity, and risks to children from current levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds in the USA. Food Chem Toxicol. 2006;44:601–615. [PubMed: 16176855] [CrossRef]
• Coggon D, Pannett B, Winter P. Mortality and incidence of cancer at four factories making phenoxy herbicides. Br J Ind Med. 1991;48:173–178. [PMC free article: PMC1035345] [PubMed: 2015208]
• Cogliano VJ. Assessing the cancer risk from environmental PCBs. Environ Health Perspect. 1998;106:317–323. [PMC free article: PMC1532993] [PubMed: 9618347]
• Collins JJ, Bodner K, Haidar S, et al. Chlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyl profiles of workers with trichlorophenol and pentachlorophenol exposures. Chemosphere. 2008;73:S284–S289. [PubMed: 18442847] [CrossRef]
• Collins JJ, Bodner KM, Wilken M, et al. Serum concentrations of chlorinated dibenzo-p-dioxins and dibenzofurans among former Michigan trichlorophenol and pentachlorophenol workers. J Expo Sci Environ Epidemiol. 2007;17:541–548. [PubMed: 17426737] [CrossRef]
• Collins JJ, Budinsky RA, Burns CJ, et al. Serum dioxin levels in former chlorophenol workers. J Expo Sci Environ Epidemiol. 2006;16:76–84. [PubMed: 16015278] [CrossRef]
• Collins JJ, Strauss ME, Levinskas GJ, Conner PR. The mortality experience of workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin in a trichlorophenol process accident. Epidemiology. 1993;4:7–13. [PubMed: 8420584]
• Cook RR, Bond GG, Olson RA, et al. Evaluation of the mortalty experience of workers exposed to the chlorinated dioxins. Chemosphere. 1986;15:1769–1776. [CrossRef]
• Costopoulou D, Vassiliadou I, Papadopoulos A, et al. Levels of dioxins, furans and PCBs in human serum and milk of people living in Greece. Chemosphere. 2006;65:1462–1469. [PubMed: 16765419]
• Crump KS, Canady R, Kogevinas M. Meta-analysis of dioxin cancer dose response for three occupational cohorts. Environ Health Perspect. 2003;111:681–687. [PMC free article: PMC1241475] [PubMed: 12727594]
• Davis BJ, McCurdy EA, Miller BD, et al. Ovarian tumors in rats induced by chronic 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment. Cancer Res. 2000;60:5414–5419. [PubMed: 11034082]
• Della Porta G, Dragani TA, Sozzi G. Carcinogenic effects of infantile and long-term 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment in the mouse. Tumori. 1987;73:99–107. [PubMed: 3576718]
• Dere E, Boverhof DR, Burgoon LD, Zacharewski TR. In vivo-in vitro toxicogenomic comparison of TCDD-elicited gene expression in Hepa1c1c7 mouse hepatoma cells and C57BL/6 hepatic tissue. BMC Genomics. 2006;7:80. [PMC free article: PMC1513214] [PubMed: 16611356]
• DiGiovanni J, Viaje A, Berry DL, et al. Tumor-initiating ability of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and Arochlor 1254 in the two-stage system of mouse skin carcinogenesis. Bull Environ Contam Toxicol. 1977;18:552–557. [PubMed: 412534]
• Dragan YP, Xu XH, Goldsworthy TL, et al. Characterization of the promotion of altered hepatic foci by 2,3,7,8-tetrachlorodibenzo-p-dioxin in the female rat. Carcinogenesis. 1992;13:1389–1395. [PubMed: 1354083]
• Dwernychuk LW, Cau HD, Hatfield CT, et al. Dioxin reservoirs in southern Viet Nam – a legacy of Agent Orange. Chemosphere. 2002;47:117–137. [PubMed: 11993628] [CrossRef]
• Ema M, Ohe N, Suzuki M, et al. Dioxin binding activities of polymorphic forms of mouse and human arylhydrocarbon receptors. J Biol Chem. 1994;269:27337–27343. [PubMed: 7961644]
• Endo F, Monsees TK, Akaza H, et al. Effects of single non-ortho, mono-ortho, and di-ortho chlorinated biphenyls on cell functions and proliferation of the human prostatic carcinoma cell line, LNCaP. Reprod Toxicol. 2003;17:229–236. [PubMed: 12642156]
• Fingerhut MA, Halperin WE, Marlow DA, et al. Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. N Engl J Med. 1991;324:212–218. [PubMed: 1985242]
• Flesch-Janys D, Berger J, Gurn P, et al. Exposure to polychlorinated dioxins and furans (PCDD/F) and mortality in a cohort of workers from a herbicide-producing plant in Hamburg, Federal Republic of Germany. Am J Epidemiol. 1995;142:1165–1175. [PubMed: 7485063]
• Flesch-Janys D, Steindorf K, Gurn P, Becher H. Estimation of the cumulated exposure to polychlorinated dibenzo-p-dioxins/furans and standardized mortality ratio analysis of cancer mortality by dose in an occupationally exposed cohort. Environ Health Perspect. 1998;106 Suppl 2:655–662. [PMC free article: PMC1533379] [PubMed: 9599713] [CrossRef]
• Gies A, Neumeier G, Rappolder M, Konietzka R. Risk assessment of dioxins and dioxin-like PCBs in food – comments by the German Federal Environmental Agency. Chemosphere. 2007;67:S344–S349. [PubMed: 17223171] [CrossRef]
• Goodman DG, Sauer RM. Hepatotoxicity and carcinogenicity in female Sprague-Dawley rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD): a pathology working group reevaluation. Regulatory Toxicology and Pharmacology. 1992;15:245–252. [PubMed: 1509118] [CrossRef]
• Green RM, Hodges NJ, Chipman JK, et al. Reactive oxygen species from the uncoupling of human cytochrome P450 1B1 may contribute to the carcinogenicity of dioxin-like polychlorinated biphenyls. Mutagenesis. 2008;23:457–463. [PubMed: 18583386]
• Haag-Grönlund M, Johansson N, Fransson-Steen R, et al. Interactive effects of three structurally different polychlorinated biphenyls in a rat liver tumor promotion bioassay. Toxicol Appl Pharmacol. 1998;152:153–165. [PubMed: 9772211]
• Hardell L, Sandström A. Case-control study: soft-tissue sarcomas and exposure to phenoxyacetic acids or chlorophenols. Br J Cancer. 1979;39:711–717. [PMC free article: PMC2009993] [PubMed: 444410]
• Hassoun EA, Li F, Abushaban A, Stohs SJ. Production of superoxide anion, lipid peroxidation and DNA damage in the hepatic and brain tissues of rats after subchronic exposure to mixtures of TCDD and its congeners. J Appl Toxicol. 2001;21:211–219. [PubMed: 11404832]
• Hassoun EA, Wang H, Abushaban A, Stohs SJ. Induction of oxidative stress in the tissues of rats after chronic exposure to TCDD, 2,3,4,7,8-pentachlorodibenzofuran, and 3,3′,4,4′,5-pentachlorobiphenyl. J Toxicol Environ Health A. 2002;65:825–842. [PubMed: 12079609]
• Haws LC, Su SH, Harris M, et al. Development of a refined database of mammalian relative potency estimates for dioxin-like compounds. Toxicol Sci. 2006;89:4–30. [PubMed: 16120753]
• Hays SM, Aylward LL. Dioxin risks in perspective: past, present, and future. Regul Toxicol Pharmacol. 2003;37:202–217. [PubMed: 12726754] [CrossRef]
• Hays SM, Aylward LL, Karch NJ, Paustenbach DJ. The relative susceptibility of animals and humans to the carcinogenic hazard posed by exposure to TCDD: an analysis using standard and internal measures of dose. Chemosphere. 1997;34:1507–1522. [PubMed: 9134683] [CrossRef]
• Hébert CD, Harris MW, Elwell MR, Birnbaum LS. Relative toxicity and tumor-promoting ability of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PCDF), and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF) in hairless mice. Toxicology and Applied Pharmacology. 1990;102:362–377. [PubMed: 2300974] [CrossRef]
• Hemming H, Bager Y, Flodström S, et al. Liver tumour promoting activity of 3,4,5,3′,4′-pentachlorobiphenyl and its interaction with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Eur J Pharmacol. 1995;292:241–249. [PubMed: 7796862]
• Hennig B, Hammock BD, Slim R, et al. PCB-induced oxidative stress in endothelial cells: modulation by nutrients. Int J Hyg Environ Health. 2002;205:95–102. [PubMed: 12018021]
• Hooiveld M, Heederik DJJ, Kogevinas M, et al. Second follow-up of a Dutch cohort occupationally exposed to phenoxy herbicides, chlorophenols, and contaminants. Am J Epidemiol. 1998;147:891–901. [PubMed: 9583720]
• Huwe JK. Dioxins in food: a modern agricultural perspective. J Agric Food Chem. 2002;50:1739–1750. [PubMed: 11902908] [CrossRef]
• IARC. Some fumigants, the herbicides 2,4-D and 2,4,5-T, chlorinated dibenzodioxins and miscellaneous industrial chemicals. IARC Monogr Eval Carcinog Risk Chem Man. 1977;15:1–354. [PubMed: 330387]
• IARC. Polychlorinated biphenyls and polybrominated biphenyls. IARC Monogr Eval Carcinog Risk Chem Hum. 1978;18:1–124. [PubMed: 215509]
• IARC. Overall evaluations of carcinogenicity: an updating of IARC Monographs volumes 1 to 42. IARC Monogr Eval Carcinog Risks Hum Suppl. 1987;7:1–440. [PubMed: 3482203]
• IARC. Polychlorinated dibenzo-para-dioxins and polychlorinated dibenzofurans. IARC Monogr Eval Carcinog Risks Hum. 1997;69:1–631. [PMC free article: PMC5366851] [PubMed: 9379504]
• Kahn PC, Gochfeld M, Nygren M, et al. Dioxins and dibenzofurans in blood and adipose tissue of Agent Orange-exposed Vietnam veterans and matched controls. JAMA. 1988;259:1661–1667. [PubMed: 3343772] [CrossRef]
• Ketchum NS, Aktar FZ (1996). The Air Force health study: an epidemiologie investigation of health effects in air force personnel following exposure to herbicides, mortality update 1996. (Interim Technical Report AL/AO-TR-1996-0068). Brooks Air Force Base, Texas: Arstrong Laboratory.
• Ketchum NS, Michalek JE, Burton JE. Serum dioxin and cancer in veterans of Operation Ranch Hand. Am J Epidemiol. 1999;149:630–639. [PubMed: 10192310]
• Knerr S, Schaefer J, Both S, et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin induced cytochrome P450s alter the formation of reactive oxygen species in liver cells. Mol Nutr Food Res. 2006;50:378–384. [PubMed: 16534750]
• Kociba RJ, Keyes DG, Beyer JE, et al. Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. Toxicology and Applied Pharmacology. 1978;46:279–303. [PubMed: 734660] [CrossRef]
• Kogevinas M, Becher H, Benn T, et al. Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins. An expanded and updated international cohort study. Am J Epidemiol. 1997;145:1061–1075. [PubMed: 9199536]
• Kogevinas M, Kauppinen T, Winkelmann R, et al. Soft tissue sarcoma and non-Hodgkin’s lymphoma in workers exposed to phenoxy herbicides, chlorophenols, and dioxins: two nested case-control studies. Epidemiology. 1995;6:396–402. [PubMed: 7548348]
• Kohn MC. Biochemical mechanisms and cancer risk assessment models for dioxin. Toxicology. 1995;102:133–138. [PubMed: 7482548]
• Kopec AK, Boverhof DR, Burgoon LD, et al. Comparative toxicogenomic examination of the hepatic effects of PCB126 and TCDD in immature, ovariectomized C57BL/6 mice. Toxicol Sci. 2008;102:61–75. [PubMed: 18042819]
• Kulkarni PS, Crespo JG, Afonso CAM. Dioxins sources and current remediation technologies – a review. Environ Int. 2008;34:139–153. [PubMed: 17826831] [CrossRef]
• LaKind JS, Hays SM, Aylward LL, Naiman DQ. Perspective on serum dioxin levels in the United States: an evaluation of the NHANES data. J Expo Sci Environ Epidemiol. 2009;19:435–441. [PubMed: 18854873] [CrossRef]
• Larsen JC. Risk assessments of polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and dioxin-like polychlorinated biphenyls in food. Mol Nutr Food Res. 2006;50:885–896. [PubMed: 17009211] [CrossRef]
• Liem AK, Fürst P, Rappe C. Exposure of populations to dioxins and related compounds. Food Addit Contam. 2000;17:241–259. [PubMed: 10912239] [CrossRef]
• Lin PH, Lin CH, Huang CC, et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces oxidative stress, DNA strand breaks, and poly(ADP-ribose) polymerase-1 activation in human breast carcinoma cell lines. Toxicol Lett. 2007;172:146–158. [PubMed: 17669606]
• Lu Y, Wang X, Safe S. Interaction of 2,3,7,8-tetrachlorodibenzo-p-dioxin and retinoic acid in MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 1994;127:1–8. [PubMed: 8048042]
• Lucier GW, Tritscher A, Goldsworthy T, et al. Ovarian hormones enhance 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated increases in cell proliferation and preneoplastic foci in a two-stage model for rat hepatocarcinogenesis. Cancer Res. 1991;51:1391–1397. [PubMed: 1671757]
• Luebeck EG, Buchmann A, Stinchcombe S, et al. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on initiation and promotion of GST-P-positive foci in rat liver: A quantitative analysis of experimental data using a stochastic model. Toxicol Appl Pharmacol. 2000;167:63–73. [PubMed: 10936080]
• Lynge E. Cancer in phenoxy herbicide manufacturing workers in Denmark, 1947–87–an update. Cancer Causes Control. 1993;4:261–272. [PubMed: 8318642]
• Mandal PK. Dioxin: a review of its environmental effects and its aryl hydrocarbon receptor biology. J Comp Physiol B. 2005;175:221–230. [PubMed: 15900503] [CrossRef]
• Manz A, Berger J, Dwyer JH, et al. Cancer mortality among workers in chemical plant contaminated with dioxin. Lancet. 1991;338:959–964. [PubMed: 1681339] [CrossRef]
• Marlowe JL, Puga A. Aryl hydrocarbon receptor, cell cycle regulation, toxicity, and tumorigenesis. J Cell Biochem. 2005;96:1174–1184. [PubMed: 16211578]
• Maronpot RR, Foley JF, Takahashi K, et al. Dose response for TCDD promotion of hepatocarcinogenesis in rats initiated with DEN: histologic, biochemical, and cell proliferation endpoints. Environ Health Perspect. 1993;101:634–642. [PMC free article: PMC1519881] [PubMed: 8143597]
• Martinez JM, Afshari CA, Bushel PR, et al. Differential toxicogenomic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin in malignant and nonmalignant human airway epithelial cells. Toxicol Sci. 2002;69:409–423. [PubMed: 12377990]
• Mayes BA, McConnell EE, Neal BH, et al. Comparative carcinogenicity in Sprague-Dawley rats of the polychlorinated biphenyl mixtures Aroclors 1016, 1242, 1254, and 1260. Toxicol Sci. 1998;41:62–76. [PMC free article: PMC7107229] [PubMed: 9520342]
• McLean D, Eng A, Walls C, et al. Serum dioxin levels in former New Zealand sawmill workers twenty years after exposure to pentachlorophenol (PCP) ceased. Chemosphere. 2009;74:962–967. [PubMed: 19036402] [CrossRef]
• Meyer BK, Pray-Grant MG, Vanden Heuvel JP, Perdew GH. Hepatitis B virus X-associated protein 2 is a subunit of the unliganded aryl hydrocarbon receptor core complex and exhibits transcriptional enhancer activity. Mol Cell Biol. 1998;18:978–988. [PMC free article: PMC108810] [PubMed: 9447995]
• Michalek JE, Wolfe WH, Miner JC, et al. Indices of TCDD exposure and TCDD body burden in veterans of Operation Ranch Hand. J Expo Anal Environ Epidemiol. 1995;5:209–223. [PubMed: 7492907]
• Milbrath MO, Wenger Y, Chang CW, et al. Apparent half-lives of dioxins, furans, and polychlorinated biphenyls as a function of age, body fat, smoking status, and breast-feeding. Environ Health Perspect. 2009;117:417–425. [PMC free article: PMC2661912] [PubMed: 19337517]
• Mimura J, Fujii-Kuriyama Y. Functional role of AhR in the expression of toxic effects by TCDD. Biochim Biophys Acta. 2003;1619:263–268. [PubMed: 12573486]
• N’Jai A, Boverhof DR, Dere E, et al. Comparative temporal toxicogenomic analysis of TCDD- and TCDF-mediated hepatic effects in immature female C57BL/6 mice. Toxicol Sci. 2008;103:285–297. [PubMed: 18343893]
• Nakatani T, Okazaki K, Ogaki S, et al. Polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and coplanar polychlorinated biphenyls in human milk in Osaka City, Japan. Arch Environ Contam Toxicol. 2005;49:131–140. [PubMed: 15983863] [CrossRef]
• Nebert DW, Dalton TP, Okey AB, Gonzalez FJ. Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer. J Biol Chem. 2004;279:23847–23850. [PubMed: 15028720]
• Nebert DW, Roe AL, Dieter MZ, et al. Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. Biochem Pharmacol. 2000;59:65–85. [PubMed: 10605936]
• NIOSH (1990). National Occupational Exposure Survey (1981-83). Cincinnati, OH: National Institute for Occupational Safety and Health. Available at http://www​.cdc.gov/noes/noes3/empl0003​.html .
• Nishizumi M, Masuda Y. Enhancing effect of 2,3,4,7,8-pentachlorodibenzofuran and 1,2,3,4,7,8-hexachlorodibenzofuran on diethylnitrosamine hepatocarcinogenesis in rats. Cancer Lett. 1986;33:333–339. [PubMed: 3802062] [CrossRef]
• NTP. Carcinogenesis Bioassay of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (CAS No. 1746–01–6) in Osborne-Mendel Rats and B6C3F1 Mice (Gavage Study). Natl Toxicol Program Tech Rep Ser. 1982;209:1–195. a. [PubMed: 12778226]
• NTP. Carcinogenesis Bioassay of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (CAS No. 1746–01–6) in Swiss-Webster Mice (Dermal Study). Natl Toxicol Program Tech Rep Ser. 1982;201:1–113. b. [PubMed: 12778178]
• NTP. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TDCC); “dioxin” Rep Carcinog. 2004;11:241–243. [PubMed: 21089963]
• NTP. NTP technical report on the toxicology and carcinogenesis studies of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (CAS No. 1746–01–6) in female Harlan Sprague-Dawley rats (Gavage Studies). Natl Toxicol Program Tech Rep Ser. 2006;521:4–232. a. [PubMed: 16835633]
• NTP. Toxicology and carcinogenesis studies of 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) (Cas No. 57117–31–4) in female Harlan Sprague-Dawley rats (gavage studies). Natl Toxicol Program Tech Rep Ser. 2006;525:1–198. b. [PubMed: 17160103]
• NTP. NTP toxicology and carcinogenesis studies of 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) (CAS No. 57465–28–8) in female Harlan Sprague-Dawley rats (Gavage Studies). Natl Toxicol Program Tech Rep Ser. 2006;520:4–246. c. [PubMed: 16628245]
• NTP. Toxicology and Carcinogenesis Studies of a Mixture of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) (Cas No. 1746-01-6), 2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) (Cas No. 57117-31-4), and 3,3',4,4',5-Pentachlorobiphenyl (PCB 126) (Cas No. 57465-28-8) in Female Harlan Sprague-Dawley Rats (gavage studies). National Toxicology Program Technical Report Series. 2006;526:1–180. d. [PubMed: 17342195]
• NTP. 2009NTP toxicology and carcinogenesis studies of 2,3',4,4',5-pentachlorobiphenyl (PCB 118) (CAS No. 31508-00-6) in female Harlan Sprague-Dawley rats (Gavage Studies) National Toxicology Program Technical Report Series5591-174. [PubMed: 21383778]
• Olie K, Schecter A, Constable J, et al. Chlorinated dioxin and dibenzofuran levels in food and wildlife samples in the North and South of Vietnam. Chemosphere. 1989;19:493–496. [CrossRef]
• Onozuka D, Yoshimura T, Kaneko S, Furue M. Mortality after exposure to polychlorinated biphenyls and polychlorinated dibenzofurans: a 40-year follow-up study of Yusho patients. Am J Epidemiol. 2009;169:86–95. [PubMed: 18974082]
• Ott MG, Messerer P, Zober A. Assessment of past occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin using blood lipid analyses. Int Arch Occup Environ Health. 1993;65:1–8. [PubMed: 8354568] [CrossRef]
• Ott MG, Olson RA, Cook RR, Bond GG. Cohort mortality study of chemical workers with potential exposure to the higher chlorinated dioxins. J Occup Med. 1987;29:422–429. [PubMed: 2439670]
• Ott MG, Zober A. Cause specific mortality and cancer incidence among employees exposed to TCDD after a 1953 reactor accident. Occup Environ Med. 1996;53:606–612. [PMC free article: PMC1128557] [PubMed: 8882118] [CrossRef]
• Parzefall W. Risk assessment of dioxin contamination in human food. Food Chem Toxicol. 2002;40:1185–1189. [PubMed: 12067582] [CrossRef]
• Pastorelli R, Carpi D, Campagna R, et al. Differential expression profiling of the hepatic proteome in a rat model of dioxin resistance: correlation with genomic and transcriptomic analyses. Molecular & Cellular Proteomics. 2006;5 (5):882–894. [PubMed: 16497791]
• Peng TL, Chen J, Mao W, et al. Aryl hydrocarbon receptor pathway activation enhances gastric cancer cell invasiveness likely through a c-Jun-dependent induction of matrix metalloproteinase-9. BMC Cell Biol. 2009;10:27. [PMC free article: PMC2680824] [PubMed: 19371443]
• Pesatori AC, Consonni D, Rubagotti M, et al. Cancer incidence in the population exposed to dioxin after the “Seveso accident”: twenty years of follow-up. Environ Health. 2009;8:39. [PMC free article: PMC2754980] [PubMed: 19754930] [CrossRef]
• Poland A, Glover E, Kende AS. Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase. J Biol Chem. 1976;251:4936–4946. [PubMed: 956169]
• Portier C, Kohn M. A biologically-based model for the carcinogenic effects of TCDD in female Sprague-Dawley rats. Organohalogen Compounds. 1996;29::222–227.
• Portier CJ, Sherman CD, Kohn M, et al. Modeling the number and size of hepatic focal lesions following exposure to TCDD. Toxicol Appl Pharmacol. 1996;138:20–30. [PubMed: 8658509]
• Rao MS, Subbarao V, Prasad JD, Scarpelli DG. Carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the Syrian golden hamster. Carcinogenesis. 1988;9:1677–1679. [PubMed: 3409472] [CrossRef]
• Ray S, Swanson HI. Activation of the aryl hydrocarbon receptor by TCDD inhibits senescence: a tumor promoting event? Biochem Pharmacol. 2009;77:681–688. [PMC free article: PMC2662439] [PubMed: 19100242]
• Ryan JJ, Schecter A. Exposure of Russian phenoxy herbicide producers to dioxins. J Occup Environ Med. 2000;42:861–870. [PubMed: 10998761] [CrossRef]
• Safe S. Molecular biology of the Ah receptor and its role in carcinogenesis. Toxicol Lett. 2001;120:1–7. [PubMed: 11323156]
• Safe S, Wormke M. Inhibitory aryl hydrocarbon receptor-estrogen receptor alpha cross-talk and mechanisms of action. Chem Res Toxicol. 2003;16:807–816. [PubMed: 12870882]
• Saracci R, Kogevinas M, Bertazzi PA, et al. Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols. Lancet. 1991;338:1027–1032. [PubMed: 1681353] [CrossRef]
• Sasamoto T, Ushio F, Kikutani N, et al. Estimation of 1999–2004 dietary daily intake of PCDDs, PCDFs and dioxin-like PCBs by a total diet study in metropolitan Tokyo, Japan. Chemosphere. 2006;64:634–641. [PubMed: 16376969] [CrossRef]
• Schecter A, Birnbaum L, Ryan JJ, Constable JD. Dioxins: an overview. Environ Res. 2006;101:419–428. [PubMed: 16445906] [CrossRef]
• Schecter A, Dai LC, Päpke O, et al. Recent dioxin contamination from Agent Orange in residents of a southern Vietnam city. J Occup Environ Med. 2001;43:435–443. [PubMed: 11382178] [CrossRef]
• Schecter A, McGee H, Stanley J, Boggess K. Dioxin, dibenzofuran, and PCB including coplanar PCB levels in the blood of Vietnam veterans in the Michigan Agent Orange Study. Chemosphere. 1992;25:205–208. [CrossRef]
• Schecter A, Pavuk M, Constable JD, et al. A follow-up: high level of dioxin contamination in Vietnamese from agent orange, three decades after the end of spraying. J Occup Environ Med. 2002;44:218–220. [PubMed: 11911020] [CrossRef]
• Schecter A, Quynh HT, Pavuk M, et al. Food as a source of dioxin exposure in the residents of Bien Hoa City, Vietnam. J Occup Environ Med. 2003;45:781–788. [PubMed: 12915779] [CrossRef]
• Schecter A, Ryan JJ, Constable JD, et al. Partitioning of 2,3,7,8-chlorinated dibenzo-p-dioxins and dibenzofurans between adipose tissue and plasma lipid of 20 Massachusetts Vietnam veterans. Chemosphere. 1990;20:951–958. [CrossRef]
• Schecter A, Startin J, Wright C, et al. Congener-specific levels of dioxins and dibenzofurans in U.S. food and estimated daily dioxin toxic equivalent intake. Environ Health Perspect. 1994;102:962–966. [PMC free article: PMC1567464] [PubMed: 9738211] [CrossRef]
• Schlezinger JJ, Struntz WD, Goldstone JV, Stegeman JJ. Uncoupling of cytochrome P450 1A and stimulation of reactive oxygen species production by co-planar polychlorinated biphenyl congeners. Aquat Toxicol. 2006;77:422–432. [PubMed: 16500718]
• Schwanekamp JA, Sartor MA, Karyala S, et al. Genome-wide analyses show that nuclear and cytoplasmic RNA levels are differentially affected by dioxin. Biochim Biophys Acta. 2006;1759:388–402. [PubMed: 16962184]
• Schwarz M, Appel KE. Carcinogenic risks of dioxin: mechanistic considerations. Regul Toxicol Pharmacol. 2005;43:19–34. [PubMed: 16054739]
• Scott LLF, Unice KM, Scott P, et al. Addendum to: Evaluation of PCDD/F and dioxin-like PCB serum concentration data from the 2001–2002 National Health and Nutrition Examination Survey of the United States population. J Expo Sci Environ Epidemiol. 2008;18:524–532. [PubMed: 18368012]
• Shertzer HG, Nebert DW, Puga A, et al. Dioxin causes a sustained oxidative stress response in the mouse. Biochem Biophys Res Commun. 1998;253:44–48. [PubMed: 9875217]
• Silkworth JB, Koganti A, Illouz K, et al. Comparison of TCDD and PCB CYP1A induction sensitivities in fresh hepatocytes from human donors, sprague-dawley rats, and rhesus monkeys and HepG2 cells. Toxicol Sci. 2005;87:508–519. [PubMed: 16049271]
• Smart J, Daly AK. Variation in induced CYP1A1 levels: relationship to CYP1A1, Ah receptor and GSTM1 polymorphisms. Pharmacogenetics. 2000;10:11–24. [PubMed: 10739168]
• Smith AH, Patterson DG Jr, Warner ML, et al. Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin levels of New Zealand pesticide applicators and their implication for cancer hypotheses. J Natl Cancer Inst. 1992;84:104–108. [PubMed: 1735875] [CrossRef]
• Steenland K, Bertazzi P, Baccarelli A, Kogevinas M. Dioxin revisited: developments since the 1997 IARC classification of dioxin as a human carcinogen. Environ Health Perspect. 2004;112:1265–1268. [PMC free article: PMC1247514] [PubMed: 15345337]
• Steenland K, Deddens J, Piacitelli L. Risk assessment for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) based on an epidemiologic study. Am J Epidemiol. 2001;154:451–458. [PubMed: 11532787] [CrossRef]
• Steenland K, Piacitelli L, Deddens J, et al. Cancer, heart disease, and diabetes in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Natl Cancer Inst. 1999;91:779–786. [PubMed: 10328108] [CrossRef]
• Stohs SJ, Shara MA, Alsharif NZ, et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced oxidative stress in female rats. Toxicol Appl Pharmacol. 1990;106:126–135. [PubMed: 2251677]
• Thiess AM, Frentzel-Beyme R, Link R. Mortality study of persons exposed to dioxin in a trichlorophenol-process accident that occurred in the BASF AG on November 17, 1953. Am J Ind Med. 1982;3:179–189. [PubMed: 6215858] [CrossRef]
• Thornton AS, Oda Y, Stuart GR, et al. Mutagenicity of TCDD in Big Blue transgenic rats. Mutat Res. 2001;478:45–50. [PubMed: 11406168]
• Todaka T, Hirakawa H, Kajiwara J, et al. Concentrations of polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and dioxin-like polychlorinated biphenyls in blood and breast milk collected from 60 mothers in Sapporo City, Japan. Chemosphere. 2008;72:1152–1158. [PubMed: 18474391] [CrossRef]
• Tóth K, Somfai-Relle S, Sugár J, Bence J. Carcinogenicity testing of herbicide 2,4,5-trichlorophenoxyethanol containing dioxin and of pure dioxin in Swiss mice. Nature. 1979;278:548–549. [PubMed: 431718] [CrossRef]
• Toyoshiba H, Yamanaka T, Sone H, et al. Gene interaction network suggests dioxin induces a significant linkage between aryl hydrocarbon receptor and retinoic acid receptor beta. Environ Health Perspect. 2004;112:1217–1224. [PMC free article: PMC1277115] [PubMed: 15345368]
• Tritscher AM, Clark GC, Sewall C, et al. Persistence of TCDD-induced hepatic cell proliferation and growth of enzyme altered foci after chronic exposure followed by cessation of treatment in DEN initiated female rats. Carcinogenesis. 1995;16:2807–2811. [PubMed: 7586202]
• Tritscher AM, Mahler J, Portier CJ, et al. Induction of lung lesions in female rats following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Pathol. 2000;28:761–769. [PubMed: 11127289]
• Tritscher AM, Seacat AM, Yager JD, et al. Increased oxidative DNA damage in livers of 2,3,7,8-tetrachlorodibenzo-p-dioxin treated intact but not ovariectomized rats. Cancer Lett. 1996;98:219–225. [PubMed: 8556712]
• Tsai PC, Ko YC, Huang W, et al. Increased liver and lupus mortalities in 24-year follow-up of the Taiwanese people highly exposed to polychlorinated biphenyls and dibenzofurans. Sci Total Environ. 2007;374:216–222. [PubMed: 17257654]
• Tsutsumi T, Yanagi T, Nakamura M, et al. Update of daily intake of PCDDs, PCDFs, and dioxin-like PCBs from food in Japan. Chemosphere. 2001;45:1129–1137. [PubMed: 11695626] [CrossRef]
• Tuomisto JT, Viluksela M, Pohjanvirta R, Tuomisto J. The AH receptor and a novel gene determine acute toxic responses to TCDD: segregation of the resistant alleles to different rat lines. Toxicol Appl Pharmacol. 1999;155:71–81. [PubMed: 10036220]
• USEPA (2000a). Exposure and Human Health Reassessment of 2,3,7,8-Tetrachlorodiobenzo-p-dioxin (TCDD) and Related Compounds (September 2000 Draft). Part I: Estimating Exposure to dioxin-like compounds. Volume 2: Sources of dioxin-like compounds in the United States. EPA/600/P-00/001 Bb. U.S. Environmental Protection Agency, Washington, DC: National Center for Environmental Assessment, Office of Research and Development.
• USEPA (2000b). Exposure and Human Health Reassessment of 2,3,7,8-Tetrachlorodiobenzo-p-dioxin (TCDD) and Related Compounds (September 2000 Draft). Part I: Estimating Exposure to dioxin-like compounds. Volume 3: Properties, environmental levels and background exposures. EPA/600/P-00/001 Bc. U.S. Environmental Protection Agency, Washington, DC: National Center for Environmental Assessment, Office of Research and Development.
• USEPA (2004). Exposure and human health reassessment of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds. National Academy of Sciences Review Draft. Washington, DC: National Center for Environmental Assessment, Office of Research and Development. Available at http://www​.epa.gov/ncea​/pdfs/dioxin/nas-review.
• USEPA (2006). An Inventory of Sources and Environmental Releases of Dioxin-Like Compounds in the United States for the Years 1987, 1995, and 2000. Washington, DC: National Center for Environmental Assessment, Office of Research and Development. Available at http://www​.epa.gov/ncea/pdfs/dioxin/
• Van den Berg M, Birnbaum LS, Denison M, et al. The 2005 World Health Organization reevaluation of human and Mammalian toxic equivalency factors for dioxins and dioxin-like compounds. Toxicol Sci. 2006;93:223–241. [PMC free article: PMC2290740] [PubMed: 16829543]
• Van Miller JP, Lalich JJ, Allen JR. lncreased incidence of neoplasms in rats exposed to low levels of 2,3,7, 8-tetrachlorodibenzo-p-dioxin. Chemosphere. 1977;9:537–544. [CrossRef]
• Vezina CM, Walker NJ, Olson JR. Subchronic exposure to TCDD, PeCDF, PCB126, and PCB153: effect on hepatic gene expression. Environ Health Perspect. 2004;112:1636–1644. [PMC free article: PMC1247661] [PubMed: 15598615]
• Viluksela M, Bager Y, Tuomisto JT, et al. Liver tumor-promoting activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in TCDD-sensitive and TCDD-resistant rat strains. Cancer Res. 2000;60:6911–6920. [PubMed: 11156390]
• Vondrácek J, Machala M, Bryja V, et al. Aryl hydrocarbon receptor-activating polychlorinated biphenyls and their hydroxylated metabolites induce cell proliferation in contact-inhibited rat liver epithelial cells. Toxicol Sci. 2005;83:53–63. [PubMed: 15483185]
• Waern F, Flodström S, Busk L, et al. Relative liver tumour promoting activity and toxicity of some polychlorinated dibenzo-p-dioxin- and dibenzofuran-congeners in female Sprague-Dawley rats. Pharmacol Toxicol. 1991;69:450–458. [PubMed: 1766921] [CrossRef]
• Walker NJ. Unraveling the complexities of the mechanism of action of dioxins. Toxicol Sci. 2007;95:297–299. [PubMed: 17297723]
• Walker NJ, Crockett PW, Nyska A, et al. Dose-additive carcinogenicity of a defined mixture of “dioxin-like compounds”. Environ Health Perspect. 2005;113:43–48. [PMC free article: PMC1253708] [PubMed: 15626646]
• Walker NJ, Yoshizawa K, Miller RA, et al. Pulmonary lesions in female Harlan Sprague-Dawley rats following two-year oral treatment with dioxin-like compounds. Toxicol Pathol. 2007;35:880–889. [PMC free article: PMC2633090] [PubMed: 18098034]
• Wyde ME, Braen AP, Hejtmancik M, et al. Oral and dermal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces cutaneous papillomas and squamous cell carcinomas in female hemizygous Tg.AC transgenic mice. Toxicological Sciences. 2004;82:34–45. [PubMed: 15282402] [CrossRef]
• Wyde ME, Wong VA, Kim AH, et al. Induction of hepatic 8-oxo-deoxyguanosine adducts by 2,3,7,8-tetrachlorodibenzo-p-dioxin in Sprague-Dawley rats is female-specific and estrogen-dependent. Chem Res Toxicol. 2001;14:849–855. [PubMed: 11453731]
• Yoshida R, Ogawa Y. Oxidative stress induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin: an application of oxidative stress markers to cancer risk assessment of dioxins. Ind Health. 2000;38:5–14. [PubMed: 10680305]
• Yoshimura T. Yusho in Japan. Ind Health. 2003;41:139–148. [PubMed: 12916743] [CrossRef]
• Yoshizawa K, Walker NJ, Jokinen MP, et al. Gingival carcinogenicity in female Harlan Sprague-Dawley rats following two-year oral treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like compounds. Toxicological Sciences. 2005;83:64–77. [PubMed: 15509667] [CrossRef]
• Zack JA, Gaffey WR (1983). A mortality study of workers employed at the Monsanto Company plant in Nitro, West Virginia. In: Human and Environmental Risks of Chlorinated Dioxins and Related Compounds. Tucker R, Young A, Grey A, editors. New York: Plenum Press, pp. 575–591.
• Zack JA, Suskind RR. The mortality experience of workers exposed to tetrachlorodibenzodioxin in a trichlorophenol process accident. J Occup Med. 1980;22:11–14. [PubMed: 6444441] [CrossRef]
• Zook DR, Rappe C (1994) Environmental sources, distribution, and fate of polychlorinated dibenzodioxins, dibenzofurans, and related organochlorines. In: Schecter, A., ed., Dioxins and Health. New York, Plenum Press, pp. 80-113.
• Zubero MB, Ibarluzea JM, Aurrekoetxea JJ, et al. Serum levels of polychlorinated dibenzodioxins and dibenzofurans and PCBs in the general population living near an urban waste treatment plant in Biscay, Basque Country. Chemosphere. 2009;76:784–791. [PubMed: 19482333]