S. M. Whitaker and L. B. Willett1
The Ohio State University Department of Animal Sciences
Polychlorinated dibenzo-p-dioxins (PCDD) and polychlorinated dibenzofurans (PCDF) are two related families of organochlorine compounds that are often referred to collectively as dioxins or furans. These families of persistent and lipophilic chemicals recently have become very important in environmental and health evaluations. These compounds are easily formed as unwanted by-products of many commercial reactions, and they have become widespread throughout our environment. Polychlorinated dibenzo-p-dioxins and PCDF are extremely lipophilic, resistant to degradation, and accumulate within the fat of animals and humans alike. Once these chemicals are released into the environment or taken up by biological tissues, they are extremely difficult to eliminate. Lactation is the most efficient route of excretion. The toxicity of these compounds are species- and chemical-structure (congener) specific. The 2,3,7,8-tetrachlorinated dibenzo-p-dioxin (TCDD) congener is considered to be the most toxic of all of the PCDD and PCDF congeners. Even small amounts of exposure to this congener can have serious health repercussions. Other PCDD and PCDF congeners are not as toxic as TCDD, but they also are toxic in small doses. The relative toxicity of these congeners is rated by "International Toxic Equivalent Factors" (I-TEF). Exposure to these chemicals should be kept as low as possible due to their potential health risks. Some of the health effects seen with exposure to these compounds have been liver enlargement, liver lesions, immunotoxicity, a wasting syndrome, thymic and spleen atrophy, tissue specific hypo- and hyperplastic responses, carcinogenesis, endocrine disruption, and in extreme cases, death. Much more research is needed to understand the movement of these environmental chemicals through food-producing livestock and into human foods.
The early 1999 "dioxin" contamination of livestock feed and subsequently livestock and the food products they produced in Belgian had a devastating financial impact. This unfortunate incident renewed questions of food safety. Although many of the details of the source of contamination and the quantities of the chemical actually reaching human food are unclear, at the time of this report, it is evident that most people have little knowledge about what dioxins actually are, where they originate, or how they enter the food chain.
Because the aforementioned Belgian incident had far-reaching implications, including the recall and destruction of large quantities of nearly all classes of food products of animal origin and the imposition of international trade restrictions on foods of animal origin, it is pertinent to provide some background information on dioxins and the closely related furan compounds. As part of our ongoing research program on dioxins and dioxin-like compounds, a review of the occurrence, fate, and toxicity of these compounds was published in a recent thesis (Whitaker, 1998). Portions of that review have been excerpted to provide a better understanding of the impact of this class of environmental contaminants on food-producing cattle.
Polychlorinated Dibenzo-p-Dioxins and Polychlorinated Dibenzofurans
The terms "dioxins" and "furans" are actually popularized misnomers for the actual scientific identification of these polyhalogenated compounds. The scientific names are polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans, and they are two related families of organochlorine compounds. These families of persistent and lipophilic chemicals recently became very important in environmental and health evaluations. These compounds easily are formed as unwanted by-products of many commercial reactions, and they became widespread throughout our environment (Nygren et al., 1986; Safe, 1998; Tai et al., 1993; Weber and Birnbaum, 1985). Polychlorinated dibenzo-p-dioxins and PCDF are extremely lipophilic and resistant to degradation (Fries, 1995a; McLachlan et al., 1990). They accumulate within the fat of animals and humans alike (Fries, 1995a; Safe, 1998; Schecter et al., 1991). Once these chemicals are released into the environment or taken up by biological tissues, they are extremely difficult to eliminate.
Formation and Structure
Polychlorinated dibenzo-p-dioxins and PCDF are chlorinated benzene compounds. The only difference between these two families of compounds is the connection between the two benzene rings. Polychlorinated dibenzo-p-dioxins are connected by a bridge containing two oxygens; PCDF are connected by a bridge containing only one oxygen (Nygren et al., 1986). Different congeners and positional isomers are formed by altering the placement of the chlorine atoms on the benzene rings. The numbering of the possible chlorination sites is shown in Figures 1 and 2. In all, there are 75 different PCDD congeners possible and 135 different PCDF congeners possible (Fries, 1995a; Nygren et al., 1986; Roeder et al., 1998). The most toxic out of all of these possible congeners are the congeners that have a 2,3,7,8-chlorine substitution pattern (Fries, 1995a; Roeder et al., 1998). These congeners are said to be coplanar.
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| Figure 1. The chemical structure of a polychlorinated dibenzo-p-dioxin where chlorine can be located at any or all of the numbered positions. |
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| Figure 2. The chemical structure of a polychlorinated dibenzofuran where chlorine can be located at any or all of the numbered positions. |
Many different types of industrial reactions create PCDD and PCDF. These compounds are formed as impurities during the manufacturing process of other compounds (Feil and Ellis, 1998; Nygren et al., 1986; Roeder et al., 1998). The manufacturing process for many herbicides, pesticides, and insecticides, including the defoliant, agent orange, and the wood preservative, pentachlorophenol, produce PCDD and PCDF as unwanted by-products (Fries, 1995a; Nygren et al., 1986; Roeder et al., 1998). Other common sources of PCDD and PCDF include waste incinerators, leaded gasoline, paper mills, fireplaces, natural fires, coal-powered operations, and sewage treatment plants (Feil and Ellis, 1998; Roeder et al., 1998).
Exposure, Deposition, and Excretion
Most livestock exposure results from accidental contamination of a feed source, housing in a facility constructed of pentachlorophenol-treated wood, or environmental contamination of forages with emissions from a source of combustion. As with organochlorine pesticides (Willett et al., 1993), fallout on forages has been an important source of exposure to cattle (Rappe et al., 1987; Tuinstra et al., 1992). Exposure to PCDD and PCDF is mostly by the oral route; therefore, it is important to understand that the oral biological availability of all of the congeners and their ability to partition into tissues is not the same (Van den Berg et al., 1994).
The theoretical absorption efficiency of most of the PCCD and PCDF congeners is approximately 80% of the ingested dose (McLachlan et al., 1990). The more highly chlorinated organohalogen congeners are less efficiently absorbed. However, absorption efficiency is also dependent on the type of contaminated particle ingested and on the physical characteristics of the congener, such as molecular size, weight, and solubility (Fries, 1995b; Van den Berg et al., 1994). There is decreased absorption associated with the hepta- and octa-chlorinated congeners, which appears to be a result of their physical characteristics (Fries, 1995b).
A general estimate of the bioavailability of some PCDD and PCDF congeners has been suggested. Approximately 25 to 50% of an oral dose was absorbed by rats when the congeners contained four to six chlorine substitutions (Van den Berg et al., 1994). Studies suggested that somewhere between two to 15% of an oral dose was absorbed when the congeners administered contained seven to eight chlorine substitutions (Birnbaum and Couture, 1988; Van den Berg et al., 1994). These absorption relationships are very similar to what was shown for other polyhalogenated aromatic compounds when fed to cattle (Willett and Irving, 1976; Willett et al., 1987).
Absorption characteristics of PCDD and PCDF are also extremely dependent upon the environmental matrix in which the dose is administered (Fries, 1995b; Nessel et al., 1992, Van den Berg et al., 1994). Nessel et al. (1992) discovered that the pulmonary bioavailability of a TCDD dose was 100% when rats were exposed to TCDD-enriched soil particles. Rose et al. (1976) reported only 75 to 80% of an orally administered TCDD was absorbed when administered in corn oil. Absorption efficiency of a TCDD dose dropped to approximately 50% when administered as part of the normal rat chow diet (Fries and Marrow, 1975). Oral absorption of TCDD from soil was reported to be as low as 40%, and absorption from fly ash was even lower at 30% (Fries, 1991; Fries and Paustenbach, 1990). Once absorbed, PCDD and PCDF were transported through the blood bound to proteins or lipoproteins to the storage sites of adipose tissue and the liver where they accumulated (Patterson et al., 1989; Schecter et al., 1990).
Half-life kinetics (the time required for one-half of the compound to be metabolized and/or excreted) of these compounds are difficult to determine because they are dependent upon tissue redistribution of the chemical, lactation status, body condition, age, species, and sex of the animal. Half-life determinations are also dependent on the congener being studied, the administration vehicle, and the length of exposure. Due to all of the complicating factors in determining kinetics, results among studies differ dramatically.
The half-life of TCDD has been reported to be anywhere from 10 to 43 days in small animals and up to five to 11 years in humans (Flesch et al., 1996; Pirkle et al., 1989; Poiger and Schlatter, 1986; Nygren et al., 1986; Schlatter, 1991; Wolfe et al., 1994). Some studies estimate the half-lives of the hexa- (HxCDD), hepta- (HpCDD), and octa-CDD (OCDD) congeners to be only three to six years in humans (Gorski et al., 1984) and are probably much the same for nonlactating cattle. Schlatter (1991) reported the half-lives of PeCDD, HxCDD, HpCDD, and OCDD in humans to be approximately five, 15, 25, and 50 years, respectively. Results from all of these studies were inconclusive. Clearly, no one half-life can be estimated because of all of the confounding factors involved in absorption, storage, and elimination of these compounds. All of these results suggest that PCDD and PCDF have the potential to accumulate in biological tissue, and even if exposure is stopped, elimination is a long, slow process.
Feces is the major route of elimination. This route of elimination appears to be due to the unabsorbed material being eliminated within 48 hours of the dose. Later, fecal elimination appeared to be due to the compounds being metabolized by the liver where the toxins were secreted into the bile for elimination (Van den Berg et al., 1994). The amounts excreted after exposure by this route were very small. Likewise, very small amounts of PCDD and PCDF were excreted in a conjugated form by means of the urine.
Pre- and postnatal transfer are other potentially important routes of elimination. Milk and placental transfer were studied in a number of species. It was reported that the transfer of PCDD and PCDF via the placenta was low, but PCDD and PCDF transfer via the milk was found to be extremely high (Firestone et al., 1979; Jensen and Hummel, 1982; Krowke et al., 1990; Nau and Bass, 1981; Nau et al., 1986; Van den Berg et al., 1987; Weber and Birnbaum, 1985). Polychlorinated dibenzo-p-dioxins and PCDF easily were transferred during lactation, which resulted in an elimination rate that was approximately twice as fast in females that were lactating compared to females that were not lactating (Feil and Ellis, 1998; Weber and Birnbaum, 1985). The high transfer associated with lactation of some congeners resulted in concentrations of some PCDD and PCDF congeners in the offspring that were equal to or higher than the concentration in the mother (Krowke et al., 1990; Van den Berg et al., 1987). Studies conducted on transfer during lactation raised concern because the exposed, developing offspring could be more sensitive to these toxic chemicals. At the same time, the chemicals were being concentrated within their systems. Another concern was that the congener most efficiently transferred in the milk was the highly toxic TCDD congener. The most poorly transferred congeners were HpCDF, OCDD, and octachlorinated dibenzofuran (OCDF). It appeared that, with the increasing chlorination, these compounds were not transferred efficiently through milk (Krowke et al., 1990, Olling et al., 1991; Van den Berg et al., 1987).
The wide range of health effects of PCDD and PCDF, even though species-, conager-, and sex-dependent, covers a whole spectrum of potentially serious health problems that can occur if sufficient residue is present. Differences in species sensitivity exist and have been suggested to be a result of either different body fat compositions by species or of differences in metabolism (Geyer et al., 1990; Roeder et al., 1998). Although differences exist in the amount of chemical required to elicit a toxic response, once toxicosis is induced, the toxic effects observed were very similar. The type of exposure (acute vs. chronic) and the amount of exposure were also important determinants of the ultimate toxic effects of PCDD and PCDF exposure.
Toxic exposure to PCDD and PCDF congeners has been shown to cause liver enlargement, liver lesions, immunotoxicity, a wasting syndrome, thymic and spleen atrophy, tissue specific hypo- and hyperplastic responses, carcinogenesis, endocrine disruption, and in extreme cases, death (Goldstein and Safe, 1989; Nygren et al., 1986; Poland and Knutson, 1982; Safe, 1986, 1990). Toxic effects of the skin include chloracne, hypertrichosis, and hyperpigmentation (Bleiberg et al., 1964, Poland et al., 1971).
Health effects can be observed for years after the initial exposure. In an incident where a horse arena was sprayed with waste oil sludge containing TCDD, horses showed signs of toxicosis for 2.5 years after exposure (Kerkvliet et al., 1992). The clinical symptoms observed were chronic weight loss, hair loss, skin disorders, colic, dark urine, gross hematuria, conjunctivitis, joint stiffness, and laminitis (Kerkvliet et al., 1992).
The relative toxicity of all of the possible PCDD and PCDF congeners was studied, and a system of comparative toxicity was developed. To determine exposure and toxicity risks associated with these compounds, a numbering system based on I-TEF was devised. International toxic equivalency factors were based on the binding affinity of the congeners to the Ah receptor (Fries, 1995a). Because TCDD is the most toxic congener, it arbitrarily was given an I-TEF of 1 (Fries, 1995a). The other PCDD/PCDF congeners were ranked in relation to TCDD. International toxic equivalency factors for the most important congeners are shown in Table 1.
Table 1. International Toxic Equivalency Factors for the Most Toxic Polychlorinated Dibenzo-p-Dioxin and Polychlorinated Dibenzofuran Congeners. |
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|---|---|
| Congeners | International Toxic Equivalency Factor |
| 2,3,7,8-tetrachlorodibenzo-p-dioxin | 1.0 |
| 1,2,3,7,8-pentachlorodibenzo-p-dioxin | 0.5 |
| 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin | 0.1 |
| 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin | 0.1 |
| 1,2,3,7,8,9-hexachlorodibenzo-p-dioxin | 0.1 |
| 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin | 0.01 |
| 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin | 0.001 |
| 2,3,7,8-tetrachlorodibenzofuran | 0.1 |
| 2,3,4,7,8-pentachlorodibenzofuran | 0.5 |
| 1,2,3,4,7,8-hexachlorodibenzofuran | 0.1 |
| 1,2,3,6,7,8-hexachlorodibenzofuran | 0.1 |
| 2,3,4,6,7,8-hexachlorodibenzofuran | 0.1 |
| 1,2,3,4,6,7,8-heptachlorodibenzofuran | 0.01 |
| 1,2,3,4,6,7,8,9-octachlorodibenzofuran | 0.001 |
A sample that contains more than one congene has a toxicity reported as the toxic equivalency quotient (TEQ), which is defined as "the sum of the quantity of individual congeners multiplied by the respective TEF" (Fries, 1995a). There is some current controversy over the use of TEQ to determine exposure risk assessments due to congener differences in bioavailability (Fries, 1995b; Van den Berg et al., 1994). Toxic equivalent quotient estimations do not incorporate bioavailability into the risk calculations; therefore, the potential risk is sometimes overestimated (Safe, 1998). Other problems with the TEQ approach in determining toxicity of these compounds is that an individual is rarely exposed to only one PCDD or PCDF.
Because these compounds are formed as unwanted by-products, they usually are found in mixtures that contain a number of different PCDD and PCDF congeners and other halogenated aromatic hydrocarbons (Safe, 1986; 1998). The TEQ approach assumes only additive effects of all of these compounds when both synergistic and antagonistic effects have been documented (Safe, 1986; 1998).
An "acceptable dietary intake" value of 6 pg I-TEQ/g of PCDD or PCDF in milk fat was established by the Netherlands Government (Feil and Ellis, 1998; Tuinstra et al., 1992). Because the Food and Drug Administration did not publish specific action levels on PCDD and PCDF concentrations in food in the United States, the United States Environmental Protection Agency (U.S. EPA) suggested a human risk-specific dose of 0.5 pg, which is equivalent to a dose of 6.4 fg/kg BW/day (U.S. EPA). Doses up to 100 fg/kg BW/day were associated with a cancer risk of 1 in 1,000,000 (U.S. EPA, 1985; U.S. EPA, 1988).
Currently, studies are being conducted in the Department of Animal Sciences to better define the distribution and clearance of PCDD and similar organochlorine compounds in dairy cattle. A better understanding of these dynamic processes will assist in the prevention of future contamination and provide the basis for realistic assessments of potential transfer of these toxicants to human foods.
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1 For more information, contact at: The Ohio State University, Ohio Agricultural Research and Development Center, 128 Gerlaugh Hall, 1680 Madison Avenue, Wooster, OH 44691; (330) 263-3792, Fax (330) 263-3949; email:willett.2@osu.edu