President Viktor Yushchenko of Ukraine before and after dioxin poisoning with 2,3,7,8-TCDD (courtesy of the Associated Press). 

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... leading TCDD to be called ‘‘the most toxic man-made chemical.’’ The LD 50 for guinea pigs is 1 m g/kg body weight, but 1000 m g/kg for hamsters. The LD 50 is not known for humans, but from the results of poisoning episodes it is clearly higher than for guinea pigs. Death in laboratory animals is preceded by a wasting syndrome (Gasiewicz et al., 1980), which typically takes from 2 to 4 weeks in rodents and 6–8 weeks in nonhuman primates (Birnbaum and Tuomisto, 2000) and is not based on decreased dietary intake since pair-fed animals with matched reduced diets do not die of decreased food intake (Gasiewicz et al., 1980). While there is a great deal of species variability in the lethal dose of dioxins, other adverse effects, such as developmental toxicity, occur at similar doses in multiple vertebrate species (Birnbaum and Tuomisto, 2000). In humans and other vertebrates dioxins have been shown to be risk factors for cancer (Fingerhut et al., 1991; Steenland et al., 1999); immune deficiency (Weisglas- Kuperus et al., 2000); reproductive and developmental abnormalities (Guo et al., 2003); central and peripheral nervous system pathology (Guo et al., 2003); endocrine disruption, including diabetes (Longnecker and Michalek, 2000) and thyroid disorders (Pavuk et al., 2003); decreased pulmonary functions and bronchitis (Shigematsu et al., 1978; Nakanishi et al., 1985); altered serum testosterone level (Egeland et al., 1994); eyelid pathology, including meibomian gland hypersecretion and hyperpigmented conjunctivae; gum pigmentation (Masuda, 2003); nausea; vomiting; loss of appetite; skin rashes, including, rarely, chloracne or acne caused by chlorine-containing organic chemicals; hypertrichosis; liver damage; elevated serum cholesterol and triglycerides (Kimbrough et al., 1977); and enamel hypomineralization of permanent first molars in children (Alaluusua et al., 2004). Table 3 summarizes these clinical manifestations. An increased risk of mortality was associated with high levels of occupational exposure to dioxins with acute ischemic cardiovascular events (Flesch- Janys et al., 1995). Transient acute health effects including headache, pruritis, fatigue, irritability, inability to have erections or ejaculations, personality changes, pain in the abdomen or extremities, diarrhea, and insomnia have been reported, especially following industrial exposures (Kimbrough and Jensen, 1989). Reviews of the human effects are largely from occupational and epidemiological studies (WHO, 1997; CDC, 1998; IOM, 2001, 2005; Schecter and Gasiewicz, 2003; EPA, 2004). Because dioxins are highly toxic, it would not be moral, ethical, or legal to knowingly dose humans with these compounds. Instead, human studies have largely depended upon unfortunate incidents such as exposures of chemical workers (Oliver, 1975; Schecter and Ryan, 1992), contaminated rice oil used for cooking (Masuda, 2003), people living near chemical factory explosions, for exam- ple, in Seveso in 1976 (Bertazzi and di Domenico, 2003), and Vietnam veterans who sprayed Agent Orange (Michalek et al., 1990; Pavuk et al., 2003, 2005). In addition, since dioxin contamination is currently ubiquitous, positive epidemiological findings have been observed in children born to women whose TEQ levels are at the high end of the general population (Koopman-Esseboom et al., 1994; Weisglas-Kuperus et al., 2000). Intentional dioxin poisoning has been described on only two occasions (Geusau et al., 2001a; BBC, 2004; Chivers, 2004). In a deliberate poisoning at a textile institute in Vienna in 1997, three workers with measured levels of TCDD up to 1000 ppt lipid in blood had few if any clinical symptoms (Geusau et al., 2001a). [ Note: The level of TCDD in the US and European general populations today is approximately 1–2 ppt lipid, while the total TEQ is about 20–30 ppt lipid (Schecter and Pa ̈ pke, 1998). These levels have been declining in the past 2 decades (Schecter et al., 1989; EPA, 2004).] There were two more highly poisoned individuals, one with the highest TCDD value ever measured in blood lipid, 144,000 ppt, and another with 27,000 ppt lipid. The most highly exposed woman felt very ill, developed chloracne with pruritis, experienced fatigue and pain in the extremities, and was sick for 2 years (Geusau et al., 2001a). The other intentional poisoning recently documented was that of the current Ukrainian president, Victor Yushchenko (BBC, 2004; Chivers, 2004; Fackelmann, 2004). A red skin rash or erythema sometimes followed by an acneform eruption over the face and body was first noted in groups of exposed chemical workers in the late 1800s and early 1900s. This acne eruption became known as chloracne, or acne caused by chlorinated synthetic organic chemicals such as polychlorinated napthalenes, dioxins, PCDFs, PCBs, and hexachlorobenzenes (Herxheimer, 1899; Kimmig and Schulz, 1957). Chloracne, in the past referred to as the hallmark of dioxin exposure, is shown in Figs. 2–6. Fig. 2 shows Ukraine President Viktor Yushchenko before and after he developed chloracne from a deliberate poisoning with TCDD. Fig. 3 shows the face of a child from Seveso, Italy, exposed to TCDD in whom chloracne and increased reddish facial pigmentation can be observed. Fig. 4 shows the back of a woman with chloracne and brownish hyperpigmentation who was exposed decades earlier to PCDFs and PCBs in the Yusho rice oil incident. Fig. 5 shows the dark ‘‘cola-colored’’ hyperpigmentation characteristically seen in some Yusho babies. Fig. 6 shows chloracne and hyperpigmentation on the face of a Japanese incinerator worker who was exposed predominantly to PCDFs. His blood congener analysis is shown in Table 2. Chloracne is a relatively insensitive and rare pathology following high-dose dioxin contamination, usually requiring blood lipid concentrations greater than 8000–10,000 ppt (Mocarelli et al., 1991; Needham et al., 1997; Landi et al., 1998; Bertazzi and di Domenico, 2003). Most persons with exposures up to 8000 ppt lipid and even some with higher levels did not develop chloracne in the Seveso incident. It was predominantly children who developed chloracne. While chloracne sometimes lasts for years, even decades in some cohorts, the cases usually resolved within 1 year in the Seveso children. In another population, Coenraads et al. (1999) found that chloracne occurred in all seven Chinese chemical workers who had TEQ blood lipid levels greater than 1000 ppt after producing the biocides pentachlorophenol and hexachlor- ocyclohexane (Coenraads et al., 1999). Treatment for chloracne does not differ from treatment of common acne. Various approaches to lowering dioxin body burden, including dietary intake of mineral oil (Moser and McLachlan, 1999), activated charcoal (Araki, 1974), rice bran oil (Ilda, 1995), or the fat substitute Olestra (Geusau et al., 1999, 2002), as well as cutaneous elimination by the application of petrolatum have been tried to reduce dioxin body burden in dioxin-exposed persons with little or no clinical success (Geusau et al., 2001b). Since dioxins are lipid soluble, lactation can reduce the level in the nursing woman (Schecter et al., 1996). Unfortunately, this leads to increased exposure of the nursing infant. Although the original sources of dioxins are largely industrial, the general population’s route of exposure is almost exclusively through consumption of animal foods including meat, fish, and dairy products (Startin and Rose, 2003; EPA, 2004). Because dioxins are fat soluble, lowering fat content in food can reduce the amount of dioxin intake. Skim milk will have no dioxins, whereas milk with fat will contain higher levels. Low-fat yogurt will typically contain far less dioxins than ice cream (Schecter et al., 2001b). Broiling meat or fish and allowing the fat to drip from the food will markedly decrease the remaining amount of dioxins present (Schecter et al., 1998). Vegetables and fruit are typically very low in dioxins; therefore, long-term vegans may have much lower body burden of dioxins than people consuming animal-based products (Schecter and Pa ̈ pke, 1998). The average US adult currently has a daily TEQ intake of approximately 1 pg/kg, lower than a decade ago, whereas a nursing infant has an average TEQ intake of 35–53 pg/kg/day (Schecter et al., 1994; EPA, 2004). Fortunately, because of the rapid growth of the infant and more rapid elimination, the body burden of the infant usually does not exceed that of the adult by more than about threefold (Lorber and Phillips, 2002). The older occupational medicine literature is most useful with respect to describing acute reactions to high doses of dioxins and related chlorinated organics. A number of scientific texts provide good summaries of the dioxin literature (Kimbrough and Jensen, 1989; Schecter and Gasiewicz, 2003). A number of government and other documents also provide relatively up-to-date and comprehensive reviews. The EPA has a very large draft review of dioxins currently available only electronically (EPA, 2004). The IARC published an excellent review several years ago, but focused on cancer more than other adverse health outcomes (WHO, 1997). The WHO reviewed the risk of individual dioxins in 1998, publishing background infor- mation and conclusions regarding TEFs (Van den Berg et al., 2000). The Institute of Medicine of the National Academy of Sciences on contract from the Office of Veterans’ Affairs publishes a review and evaluation of the literature every 2 years, focusing on possible health effects of dioxin or herbicides to which US veterans of the Vietnam war might have been exposed (IOM, 2005). Some of the references which exist are relatively comprehensive but they are generally not clinically oriented (Kimbrough and Jensen, 1989; Schecter and Gasiewicz, 2003). The Agency for Toxic Substances and Disease Registry of the CDC publishes periodic updates in their Toxicological Profiles which include ...

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... humans and other vertebrates dioxins have been shown to be risk factors for cancer (Fingerhut et al., 1991;Steenland et al., 1999); immune deficiency (Weisglas- Kuperus et al., 2000); reproductive and developmental abnormalities (Guo et al., 2003); central and peripheral nervous system pathology (Guo et al., 2003); endocrine disruption, including diabetes (Longnecker and Michalek, 2000) and thyroid disorders ( Pavuk et al., 2003); decreased pulmonary functions and bronchitis ( Shigematsu et al., 1978;Nakanishi et al., 1985); altered serum testosterone level (Egeland et al., 1994); eyelid pathology, including meibomian gland hypersecretion and hyperpigmented conjunctivae; gum pigmentation (Masuda, 2003) Kimbrough et al., 1977); and enamel hypomineralization of permanent first molars in children ( Alaluusua et al., 2004). Table 3 (Kimbrough and Jensen, 1989). ...

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... humans and other vertebrates dioxins have been shown to be risk factors for cancer (Fingerhut et al., 1991;Steenland et al., 1999); immune deficiency (Weisglas- Kuperus et al., 2000); reproductive and developmental abnormalities (Guo et al., 2003); central and peripheral nervous system pathology (Guo et al., 2003); endocrine disruption, including diabetes (Longnecker and Michalek, 2000) and thyroid disorders ( Pavuk et al., 2003); decreased pulmonary functions and bronchitis ( Shigematsu et al., 1978;Nakanishi et al., 1985); altered serum testosterone level (Egeland et al., 1994); eyelid pathology, including meibomian gland hypersecretion and hyperpigmented conjunctivae; gum pigmentation (Masuda, 2003) Kimbrough et al., 1977); and enamel hypomineralization of permanent first molars in children ( Alaluusua et al., 2004). Table 3 (Kimbrough and Jensen, 1989). ...

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... 1800s and early 1900s. This acne eruption became known as chloracne, or acne caused by chlorinated synthetic organic chemicals such as polychlorinated napthalenes, dioxins, PCDFs, PCBs, and hexachlorobenzenes (Herxheimer, 1899;Kimmig and Schulz, 1957). Chloracne, in the past referred to as the hallmark of dioxin exposure, is shown in Figs. 2-6. Fig. 2 shows Ukraine President Viktor Yush- chenko before and after he developed chloracne from a deliberate poisoning with TCDD. Fig. 3 shows the face of a child from Seveso, Italy, exposed to TCDD in whom chloracne and increased reddish facial pigmentation can be observed. Fig. 4 shows the back of a woman with chloracne and brownish ...