PBBs, PCBs, And Dioxins In Food Animals, Their Public Health Implications

CHEMICAL FOOD BORNE HAZARDS AND THEIR CONTROL

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PBBs, PCBs, AND DIOXINS IN FOOD ANIMALS, THEIR PUBLIC HEALTH IMPLICATIONS Marcia L. Headrick, DVM, MPH; Katherine Hollinger, DVM, MPH; Randall A. Lovell, DVM, PhD; and John C. Matheson, MSPH

Polybrominated biphenyls (PBBs), Polychlorinated biphenyls (PCBs), and dioxins belong to a group of related chemical compounds for which evidence of toxic potential in food animals and humans has been demonstrated by laboratory research and investigation of accidental exposures. Exposure of food animals and ultimately humans to PBBs, PCBs, dioxins, and related compounds often occurs unwittingly through environmental sources or animal feed. The recent discovery of dioxins in ball clay used as an anticaking compound in animal feeds is an important reminder that vigilance must be maintained for potential sources of contamination from these compounds. In this article, the ball clay incident is described as well as examples of known accidental exposures to PBBs and PCBs. Background information regarding the mechanism of toxicity and effects in animals and humans is also included. POLYBROMINATED BIPHENYLS

The largest exposure of food animals and humans to PBBs occurred in Michigan in the mid-1970s. The animal exposure occurred through From the Epidemiology Team, Division of Epidemiology and Surveillance (MLH, KH), Feed Safety Team, Division of Animal Feeds (RAL), Office of Surveillance and Compliance OCM), Center for Veterinary Medicine, United States Food and Drug Administration, Rockville, Maryland

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contamination of feed with a fire retardant manufactured with PBBs. The fire retardant was accidentally introduced into the animal feed when it was confused with a similarly packaged magnesium oxide feed supplement. Dairy cattle, pigs, sheep, and chickens were exposed to the contaminated feed. Human exposure occurred when milk, dry milk products, cheese, butter, and meat from the affected animals were consumed. 12 Sources of Contamination and Animal Exposure

PBB is no longer manufactured in the United States. Its sale was outlawed in Michigan; however, before production was stopped in the United States, an estimated 6 to 11 million pounds were produced and incorporated into plastic products such as housings for business machines, radios, televisions, thermostats, shavers, hand tools, and miscellaneous small automotive parts. Only a small portion of the total production of PBBs was incorporated into the animal feed that accounted for the known contamination in Michigan. The fate of all the materials that were sold in commerce remains unknown. 36 PBBs are still manufactured for use as a flame retardant in electronic equipment, plastics, building materials, and carpets outside the United States. For example, in the Netherlands, the annual consumption of PBBs is 250 tons per year. Sweden consumes 1400 to 2000 tons per year of PBBs and PBDEs combined, and Japan consumes approximately 22,100 tons per year. 28 Structure and Toxicologic Mechanisms

To understand the public health implications of PBB contamination, a basic understanding of its structure, the toxicologic mechanisms of its effects on animals, and its behavior in the environment are needed. The basic structure of PBB is two substituted aromatic hydrocarbon ring structures, with bromine as the substitution (Fig. 1). PBB and PCB are similar in their structures and would be expected to have similar toxicologic properties; however, this is not always the case. 5 The main environmental properties and mechanisms of toxicity of the PBBs are similar to

5'

6'

6

5

Figure 1. Basic molecular structure of PBBs and PCBs.

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those of the structurally related PCBs and dibenzodioxins; however, different congeners behave differently in the environment and show large differences in toxicity.28 PBB is stable, resists organic degradation, is insoluble in water,28 and is highly lipophilic. 33 Because PBB is resistant to degradation, it may accumulate to high levels in the food chain. Also, because PBB is virtually insoluble in water, it may contaminate bodies of water from run-off or dumping for an indeterminate amount of time. The Pine River in Michigan was contaminated during the 1970s exposure. In 1988, sediment core samples still contained PBBs. Over an extended time period, PBBs can be degraded. About 10% to 12% of the PBBs in the Pine River core samples had degraded through reductive debromination. Microorganisms isolated from the Pine River exhibited the capability to carry out this debromination. Biomagnification of PBBs in fish and animals has been shown. PBBs with lower numbers of bromine substitutions tend to bioaccumulate at a higher rate. 28 PBBs have been shown to cross the placenta in many species, including humans. Because PBBs are highly lipophilic, they concentrate in the milk of nursing mothers, and they readily cross the blood-brain barrier. After the Michigan exposure to PBBs in 1973, by 1978, 96% of breast milk samples from women in Michigan's Lower Peninsula contained detectable levels of PBBY Because the estimated half-life of PBB in human sera is 10.8 years (95% CI, 9.2-14.7), a single exposure may create the potential for continued perinatal exposure to PBBs. Although there have been a large number of people exposed to PBBs and similar compounds, quantitative estimates of exposure have not been well developed, and relationships between exposure and adverse health outcomes have been difficult to document. 2o The epidemiologic data from studies of human adults and children exposed to high levels of PBB are somewhat inconclusive because of such factors as small sample size, the subjective nature of testing, and the lack of double-blinding in the study designs. Testing has been conducted in lab animals. These studies demonstrated growth retardation and neurobehavioral toxicity at concentrations of PBB in offspring body fat in the range of concentrations that have been reported for highly exposed human subjects with neurologic sequelae. 16 Short-term toxicity studies in rats and rabbits indicate that there is a primary effect in the liver, where PBB induces hepatocellular carcinomas and other carcinomas, and immunologic effects such as decreased immune and antibody-formation responses to virus challenge. 5, 33 Accumulation of PBB in the fetus and fetal abnormalities also occurred in rats and rabbits in toxicity studies. The effects in humans are not as clear.33 There is evidence that PBBs, PCBs, dioxins, dibenzofurans, and related compounds are not mutagenic compounds but do promote the carcinogenicity of other mutagenic compounds. Like PCBs, PBBs cause chloracne. In guinea pigs, PBBs caused thymus atrophy, hypersensitivity, decreased antibody response, and decreased resistance against infection.

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PBBs crossed the placenta and concentrated in breast milk in monkeys, causing decreased neonatal weights. Longer sexual cycles and decreased progesterone concentrations also occurred in monkeys. Malformations of fetuses occurred when high doses of PBBs were fed to rats.28 Perinatal exposure of rats to PBB resulted in growth retardation and developmental neurotoxicity.16

Effects on Animals Exposed

Exposure to PBB has caused toxic effects in every animal species tested, including humans, primates, cattle, rats, mice, mink, fish, and birds. The documented adverse effects of PBB exposure are carcinogenicity, enzyme induction, hepatotoxicity, embryotoxicity, perinatal toxicity, teratogenicity, cardiovascular effects, neurotoxicity, immunotoxicity, neprotoxicity, tissue storage, excretion in milk, persistence in the environment, thyroid abnormalities, prophyrinogenesis, interference with cognition, and lipid abnormalities. 36 Other reported effects in animals include hyperlipidemia, body weight loss, anorexia, changes in carbohydrate metabolism, and lipid peroxidation. 23 Dairy cattle exposed to PBB in Michigan exhibited numerous nonspecific signs and symptoms, such as unthriftiness, decreased milk production, abscess formation, abnormal hoof growth, and decreased appetite. Controlled studies of the effects of PBBs fed to cattle were conducted in 1975 in response to the Michigan exposure. The cattle in the 1975 study were exposed to high levels of PBB in the feed, about 10 times the dose consumed by cattle in the Michigan exposure. Signs of toxicity exhibited by the study cattle included anorexia, emaciation, dehydration, excessive lacrimation, fetal death, and hyperkeratosis.12

Diagnostic Testing and Tolerance Levels

PBBs can be detected in blood and tissue samples from exposed animals. PBBs have been found in all tissues, including whole blood, serum, bile, breast milk, placenta, cord blood, feces, and adipose tissue. 36 There is no rapid test available for the identification of PBBs in animal feed. Analysis for PBBs in animal feed requires complex laboratory testing by gas chromatography.12 After the Michigan PBB exposure, the Michigan Department of Health established an action guideline in 1976 for food products to be consumed by humans of 5 ppb in meat and 1 ppb in milk. This action guideline was set owing to the potential for carcinogenic development in humans, PBB's persistence in human tissues, and the analytic capabilities of the Michigan Department of Agriculture laboratories. 5

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Human Health Effects

A case report of a Michigan dairy farmer with documented exposure to PBBs describes multiple systemic effects culminating in cancer. Signs and symptoms initially included arthritis, peripheral nervous system problems, gastrointestinal system problems, and skin disorders. Angina, acute epigastric pain, and dysphagia were later complaints terminating with a diagnosis of esophogastric neoplasm described as an adenocarcinoma, penetrating with extensive lymphatic invasion of esophagus and stomach. Despite treatment with surgery and chemotherapy, the patient died. 36 . Experimentally, PBB is carcinogenic in rodents, but epidemiologic studies have not shown a consistent association between PBB exposure and chronic human health effects. Several studies have been conducted to determine the relationship between PBB exposure and breast cancer in women; the results have been variable. 17

Prevention and Control

PBBs are no longer manufactured in the United States; however, all PBBs previously manufactured in the United States have not been accounted for,36 and PBBs are still produced worldwide. 28 The potential for accidental contamination of animal or human food or water supplies continues. The biochemical characteristics of PBBs and related compounds result in their persistence in the environment and bioaccumulation in the food chain. PBBs have been detected in the marine food chain in the Baltic Sea, the North Sea, and the North Atlantic Ocean. Although there does not appear to be an immediate environmental risk at current levels, researchers have suggested that PBBs and related compounds be replaced with environmentally less-harmful alternatives. 28

Widespread Exposure to PBB, A Case Description

PBBs mislabeled as magnesium oxide were accidentally introduced into animal feed in Michigan in 1973. As a result, livestock throughout the state were poisoned, and people who consumed contaminated food products were exposed to PBBs. A cross-sectional survey conducted in 1978 estimated that 97% of the 9.1 million Michigan residents had detectable levels of PBB in their bodies. 17 The Michigan PBB exposure was the largest single agricultural exposure to an industrial contaminant. It resulted in the destruction of approximately P/2 million chickens, 23,000 cattle, and 5000 swine and sheep. It also resulted in the loss of about 5 million eggs, 34,000 lb of dry milk products, 18,000 lb of cheese, 2600 lb of butter, and 1500 cases

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of canned evaporated milk. Also, 865 tons of feed were destroyed, and more than 530 Michigan farms were quarantined. IS The Michigan Chemical Company began production of PBBs in 1971. The PBBs were used in the thermoplastics industry as a fire retardant. Several experimental batches of the fire retardant were produced in a powdered form and marketed as "Firemaster." The Michigan Chemical Company also began producing an animal feed supplement, magnesium oxide, which they called "Nutrimaster." The company usually packaged the two products in distinctive red- and blue-trimmed bags (red for Firemaster, blue for Nutrimaster), but because of a paper shortage, the two products were packaged for a time in identical brown paper bags, with only the trade name stenciled on the side. In May of 1973, anywhere from 750 to 2400 lb of Firemaster were shipped to the wrong place-the Farm Bureau Services' mill in Battle Creek. Because it looked like magnesium oxide (Nutrimaster), it was substituted for it. Firemaster was mixed in with several of the animal feeds at the mill, sold to farmers as top dressing for feeds, and sent on to mills in other parts of the state. The product was distributed throughout the state. This resulted in Michigan dairy cattle, pigs, sheep, and chickens becoming contaminated with PBBs. The Firemaster product was a powder and when mixed with feed, the residue tended to collect on machinery and in the mill dust. During the subsequent investigation, even samples of dust taken from a forklift's tires were positive for PBBs. Consequently, mixed feeds that had no Firemaster added still had low levels of contamination owing to the residual powder. Animals fed the Firemaster product instead of Nutrimaster became ill. The normal level of supplementation recommended for magnesium oxide was 10/0 of the ration. At that level of Firemaster, many of the animals deteriorated quickly. Reports of strange illnesses in dairy cattle began during September of 1973. They became "unthrifty," had decreased milk production, and exhibited decreased feed and reproductive efficiency. Strange abscesses developed, and there was an increase in cases of abnormal hoof growth. Ric Halbert of Banfield, Michigan, a dairy farmer whose cattle exhibited some of the most severe signs, happened to also be a chemical engineer. He took samples of his dairy cattle feed to the Food and Drug Administration's (FDA) Detroit district laboratory for analysis, thinking the problem must be owing to some heavy-metal poisoning such as lead. No lead was found, but through a long chain of events, with multiagency cooperation, the offending contaminant was identified by gas chromatograph analysis in April of 1974. Critical to the solution was an FDA chemist who knew of a company in Michigan that produced PBBs, the Michigan Chemical Company. Once the PBBs were identified, the trace back began, and the puzzle of events that resulted in the contamination of the animal feed were connected. However, a considerable amount of time had passed, and the PBBs had spread throughout the state. Many farms were quarantined, and animal disposal became a serious problem. In the late spring and summer of 1974, Michigan agriculture products potentially contaminated with PBBs were recalled from grocer shelves. 12, IS

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By this time, not only animals were being affected by the contamination. Humans were exposed when the PBB-contaminated meat, milk, or eggs reached the farmer's or consumer's table. The animal product contamination was so widespread that the majority of the Michigan population was exposed. Estimates were made that 8 million of Michigan's 9.1 million residents were carrying detectable levels of PBBs in their bodies. 40 At the request of the state of Michigan, Dr. Irving Selikoff of the Mount Sinai School of Medicine orchestrated a determination of the extent of the contamination. He tested blood and fat tissue samples from exposed men and women. He found that 98% of the samples contained PBBs. Samples of human milk from 53 mothers who gave birth in August of 1976 showed that 51, or 96 % , contained detectable PBBs in amounts ranging between 0.05 ppm to 1 ppm. 40 No acute toxic effects were ever legally proven in humans. 37 Many of the exposed persons did report a myriad of nonspecific illnesses that could possibly have been attributed to PBBs or to stress-induced illness. Owing to a lack of information on the health effects of PBB exposure, it was difficult to assess acute illness, and long-term effects were virtually unknown. 12 Michigan Cohort

To determine if chronic effects would surface, a cohort of about 4000 exposed Michigan residents was identified and followed by the Michigan Department of Public Health in conjunction with the Centers for Disease Control (CDC) and the FDA. They wanted to compare the rates of disease over time in two groups, one group having been exposed to PBBs and another group not having been exposed but living under similar conditions. Because enough controls, that is, persons not exposed to PBB, could not be obtained within the state of Michigan, 1600 Iowa farmers were recruited as controls. Demographic and exposure data were collected by interview at enrollment, with follow-ups to collect health and pregnancy information. Because the effects of PBBs were essentially unknown, specific hypotheses could not be generated. lilt was recognized from the start that much of the analysis would be descriptive or exploratory."21 In 1976 and 1977, approximately 4000 participants were enrolled from 65 Michigan counties. About half of the participants were selected from quarantined farms, and half, from families who regularly received food (meat and dairy products) directly from those quarantined or lowlevel-contaminated farms. About 3600 provided blood samples (most young children were excluded). PBB levels were assayed. Persons living on quarantined farms had the highest median levels of PBB in their serum, and persons receiving food from low-level-contaminated farms had the lowest median levels. Overall, study participants' median serum levels were lower than those of chemical workers exposed to PBBs.21 The Michigan PBB cohort has been followed now with data collec-

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tion for over 20 years. Since the original information was gathered on enrollment in the cohort, several other data collections have occurred. In 1977 and 1978, each family was re-interviewed once to update the information on symptoms, illnesses, and pregnancies. Repeat blood samples were analyzed for about half the participants. Owing to staff and funding limitations, comprehensive annual interview surveys for such a large data set could not be continued. Thus far, no significant effects of the PBB exposure have been recognized in the cohort. The observed number of deaths has not exceeded the expected number of deaths. Infant birth weight did not decrease with higher levels of PBB in the mother's serum. l l Other studies have found similar results. Studies conducted at the Environmental Sciences Laboratory, Mount Sinai School of Medicine, 3 years after the exposure, using a Wisconsin-based control, found that certain nervous and skin-related symptoms were increased in the exposed groups in 1974 and 1975, but in 1976, the incidence was not statistically higher than the baseline 1972 rates. l l A study of human workers potentially exposed to a number of chemicals did not show an increased incidence of neoplasms in populations exposed to PBBs.4I A 1995 study of 1925 women enrolled in a Michigan PBB registry suggested that the risk of breast cancer was elevated for women with serum PBB levels of 2 to 3 ppb (OR = 3.5; 95% CI, 0.9-13) and for women with serum PBB levels of 4 ppb or greater (OR = 3.1; 950/0 CI, 0.8-12) when compared with women with serum PBB levels less than 2 ppb. Results from other studies of the relationship between PBB exposure and breast cancer have been variable. I7 A recently published study of the Michigan PBB Cohort, evaluated the relationship between risk of site-specific cancer and serum PBB levels. No strong association between baseline serum PBBs and excess cancer risk was found overall. However, individual analysis of two cancer types, digestive system cancer and lymphoma, demonstrated an increasing dose response relation as PBB levels increased. No PBB is produced in the United States today. Michigan Chemical Company was the only company producing PBBs at the time of the 1970s exposure, and they ceased production. In 1977, Michigan outlawed the use, sale, or manufacture of PBB.36 The potential exists for contamination of feed or the environment by PBB or other related compounds, if caution is not exercised. POLYCHLORINATED BIPHENYLS

PCBs are small organic molecules belonging to the family of chlorinated hydrocarbons. There are 209 PCB congeners, of which approximately 100 congeners have been used in commercial applications? These compounds are chemically stable, possess fire-retardant properties, and have nonconductive electrical properties? PCBs were produced in the United States from 1929 to 1977, primarily by Monsanto Corporation, for use in a large variety of applications. Often, they were used in closed

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systems in electrical transformers, capacitors, and heat-transfer and hydraulic systems. They were also used as stabilizers in paints, polymers, and adhesives, as lubricants,lO as vehicles for pesticide application, and as agents for the suspension of pigments in carbonless copy paper. 32 Approximately 8 million pounds of PCBs were produced during the period from 1929 to 1977, and much of that was discarded with little thought of the potential environmental impact of these chemicals. The volatility of PCBs allows their evaporation from water surfaces, movement through air, and return to land and water in rain. This results in the widespread environmental dispersal of these persistent chemical toxins? PCBs are ubiquitous compounds found in a variety of foods. They tend to bioconcentrate in fat and have long physiologic half-lives. Because humans are located at the top of the food chain, they accumulate more-highly concentrated PCBs. The highest levels of these compounds are found concentrated in human adipose tissues, blood lipids, and breast milk, especially in developed countries. lO Manufactured PCBs were rarely produced as a pure congener but were instead a heterologous mixture of congeners. Various congeners demonstrate various potencies and may interact in an additive, synergistic, or antagonistic manner with other congeners. 20 Mixtures of PCBs vary in toxic potency depending on the relative proportions of congeners, and the mixtures may contain other toxic compounds, such as polychlorinated dibenzofurans (PCDFs) and dibenzo-p-dioxin (PCDD), which enhance the toxic properties of PCBs by allowing toxic effects at lower PCB exposures. Epidemiology of Human Exposure

PCBs in food represent a complex mix of congeners that are proportionately dissimilar to commercially manufactured mixtures. The different effects of specific congeners, the interactions between congeners, and the difference between food borne mixtures and commercial PCB mixtures all complicate the determination of epidemiologic associations. Associations between PCBs and specific human health effects are also made more difficult by the presence of other compounds such as PCDFs and PCDDs. Some researchers have suggested that the use of specific commercial mixtures in laboratory animal studies may be more representative of occupational exposures than of food borne exposures. Chemical Structure, Properties, and Mechanism of Action

PCBs are very stable lipophilic compounds with a low vapor pressure, low flammability, high heat capacity, and low electrical conductivity. PCB congeners have different physical and chemical properties based on the degree and position of chlorination. Those PCBs with benzene rings located in the same plane, termed coplanar configurations, may have dioxin-like activity if chlorine substitutions are located in the 3', 3, 4', 4,

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5', 5, or even 2' and 2 positions on the benzene rings. Figure 1 shows the basic structure of the PCB molecule. The mechanisms of action of PCB toxins have not yet been dearly established and are thought to be multiple in nature. 7 It is known that PCBs are inducers of mixed function oxidase enzyme systems. At high doses, PCBs may produce a fatal wasting syndrome, the mechanism of which has not been well described. Also, PCBs have been associated with hepatic tumors and are proposed promoters of carcinogenesis. Some coplanar PCB analogs, similar to dioxins such as 2,3,7,8-tetrachlorodibenzopdioxin (TCDD), bind the cytosolic aryl-hydrocarbon (Ah) receptor in in vitro studies, affecting the regulation of gene expression. Ah receptor binding decreases with increasing chlorine substitutions, which reduce the ability of the molecules to achieve a planar configuration around the biphenyl bond. The Ah receptor binding and subsequent induction of aryl hydrocarbon hydroxylase (AHH) activity affect the metabolism of steroids and other hormones and can decrease glycogen storage in the liver.22 The two systems most sensitive to PCB exposure are (1) induction of the microsomal P450 enzymes, and (2) the covalent binding to macromolecules in microsomes. These systems are affected in a dose-responserelated fashion, with the lowest levels of impact projected at 1 to 4 J.Lg/ kg/ day,32 which is above the FDA's Tolerable Daily Intake (TDI) of 1 J.Lg/kg body weight/ day.8 Steroid synthesis and thyroid hormone metabolism is P450-mediated. These hormones are sensitive to dietary PCB exposure in the parts per billion range, and the toxic effects of an exposure can last a very long time. 2o,23 Difficulty in determining the toxic effects of PCBs is compounded by the multitude of effects on diverse systems (immunotoxic, teratogenic, neurobehavioral, and reproductive effects) and diverse mechanisms of action. The sensitivity of different animal species to the toxic effects of specific PCB congeners varies, making it difficult to extrapolate findings from laboratory animal studies to man; however, when effects are noted across species, they tend to be consistent in type of effect. Human Health Effects and Sources of Human Exposure from Animal Food Products

Health effects of PCB toxicity that have been consistently demonstrated in laboratory animals are chloracne, fatty degeneration of the liver, impaired T-cell function, reduced dopamine concentrations in the midbrain, and reductions in serum T3 and T4 concentrations. Fetotoxic effects of maternal exposure to PCBs occur from cross-placental transfer of the toxins. Fetal exposure has been associated with low birth weights, increased duration of gestation, and impaired postnatal development. These effects are evident in offspring at low levels of exposure, whereas signs of maternal toxicity are not noted. 32 These effects and others have also been noted in humans in food-contamination incidents. Other proposed human health effects are increased risk of breast cancer from high concentrations of PCBs in breast adipose tissue, other endocrine disruptive capabilities, and involvement in reproductive disorders.lO

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Two very similar high-level-contamination incidents have occurred, one in Japan in the late 1960s, and another in Taiwan in 1979, where PCBs and PCDFs contaminated cooking oil. The Taiwan incident, termed yucheng, was discovered after an epidemic of chloracne, hyperpigmentation, and meibomian gland dilatation occurred in persons consuming the oil. In controlled studies of babies born after maternal exposure to the contaminated oil, in utero and lactational exposures resulted in neuroectodermal developmental abnormalities that were manifested by abnormalities of gingiva, skin, nails, teeth, and lungs. In addition to these abnormalities, cognitive developmental delays and abnormalities on behavioral assessments were reported. 32 The earlier Japanese cooking oil contamination incident, termed yusho demonstrated similar effects in more than 1600 individuals. 8 Other studies of the impact of neonatal exposure to PCBs in the Great Lakes region have indicated deficits such as low birth weight, poor short-term memory performance, and impaired cognitive processing. These effects were observed at very low levels of toxic exposure and appear to have long-term impact on intellectual function. I8, 19 These health effects are also suggested to occur at current environmental levels of exposure in the population. lo Evidence of the widespread nature of human exposure comes from surveys of human breast milk. Higher levels of PCBs are found in human breast milk in industrialized countries compared to less industrialized countries. Human milk also contains relatively higher levels of PCDDs, a frequently co-occurring compound that enhances the activity of PCBs, than are found in cow's milk. 35 Human exposure is so widespread that PCBs are detected in almost 100% of human milk samples in the United States,32 with at least one fourth of the samples carrying levels greater than the FDA's "action level" of 1.5 ppm for withdrawal of milk. 43 This places infants at the greatest risk of exposure, during gestation and while nursing. Human exposure to PCBs occurs from absorption of low doses, primarily from ingestion of fatty food, that bioaccumulate and concentrate in fat over a lifetime. The highest accumulated tissue levels are found in older individuals. Levels are higher in males than in females, and levels decline in women with increasing parity and increasing duration of lactation.34 Evidence suggests that PCBs possess estrogenic activity. High estrogen levels in women are associated with shortened follicular phases of the menstrual cycle and shortened cycle length. PCBs have recently been associated with shortened cycle length24 and have been proposed to result in feminization of males I4 that affects the reproductive capabilities of exposed populations. 7 Food is the source of 80% of human exposure to these compounds. I4 Major sources of human food borne exposure are fish, meat, and dairy products. Five PCB congeners predominate in fatty foods, and an additional three congeners predominate in freshwater fish. 7 Fish and marine products appear to be the most important dietary exposures for humans

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to PCBs, containing the highest levels of these compounds. Table 1 lists tolerable levels for PCBs in food and feed as established by the FDA. Food Animal Contamination

Sources of food animal exposure to PCBs are as varied as their uses. One example of food animal exposure involves concrete silo construction practices in the 1940s and 1950s. At that time, concrete silos were coated with a PCB-containing sealant paint. This sealant later peeled off of the walls of the silos and contaminated silage. Dairy and beef cattle were exposed to the paint in feed, and the compound was stored in their fat, to be excreted in milk and concentrate in fat, or to be consumed as meat. Food animal incidents may result from the exposure of a single animal or a flock of animals, such as geese pecking at paint chips in a barn, and have involved many animals or animal species in many states when widespread feed contamination has occurred. The signs of animal exposure to PCBs may be subtle and difficult to observe in a farm setting at typical levels of exposure. A decline in the normal aggressiveness of male herring gulls, who failed to protect their nests against predators, was apparently the result of high levels of PCB exposure from freshwater fish. 14 Laboratory animal studies have demonstrated minimal general health effects but have noted reproductive failures, diminished ability to adapt to stress or changing conditions, and activity levels that differed significantly from control animals. These signs, if observed, are nonspecific and could potentially result from numerous other causes. Often food animal exposures to PCBs occur below the levels of acute toxicity and clinical signs are not evident, and there is not always a perceptable economic impact on the health of the animals. The clinical effects of high level PCB exposures are not well documented. The most

Table 1. FDA ESTABLISHED TOLERANCE FOR PCBs IN FOOD AND FEED* Food

Milk (fat basis) Manufactured dairy products (fat basis) Poultry (fat basis) Eggs Finished feed for food-producing animals Animal feed components of animal origin, animal feed concentrates, supplements, and premixes Infant and junior foods Paper food-packaging materials Fish and shellfish (edible portion)

Level (ppm)

1.5 1.5

3.0 0.3 0.2 2.0 0.2 10.0 2.0

*21 CFR 509.30, Temporary tolerances for polychlorinated biphenyls (PCBs) and 21 CFR 109.30, Tolerances for polychlorinated biphenyls (PCBs)

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commonly observed signs in laboratory mice or chickens exposed to very high doses are loss of body weight caused by losses of fatty tissue, hyperlipidemia, anorexia, and changes in carbohydrate metabolism. The subtle nature of the signs associated with food animal exposures often preclude identification of contaminated animals prior to slaughter without organochlorine tissue-residue sampling. Sampling of adipose tissue, milk, or eggs for organochlorine residues is appropriate if toxicity is suspected. Most often, the presence of PCBs in food animals is detected through routine tissue residue testing done by the US Department of Agriculture (USDA) Food Safety and Inspection Service (FSIS). Table 2 lists some identified sources of exposure to PCBs in animals. Preventing animal exposures may be difficult, as PCBs are usually present in low concentrations and do not perceptibly alter the food or feed. The removal of material and equipment potentially containing the toxins, such as transformers, flaking paint, and chemical containers, from areas where animals are kept may help prevent exposure to PCBs.

Feed Contamination Incident-A Classic Case Description

In June of 1979, a spare electrical transformer in a hog slaughter plant in Billings, Montana was damaged, and PCBs leaked unobserved into the plant's drainage system. The PCBs and animal wastes were processed into grease and animal feed, which was distributed and fed to animals, including hogs, beef cattle, dairy cattle, chickens, and mink, before any contamination was observed. The processed products were

Table 2. PCB RESIDUES IN FOOD ANIMALS WITH IDENTIFIED SOURCES OF EXPOSURE, FROM THE NATIONAL RESIDUE MONITORING PROGRAM, 1989-1996 Animal Species

Number of Animals in Slaughter Lot

Veal calf Market hog Mature chickens

30

Young chickens

110,000

Geese Steers and heifers*

200 100

Boar*

400

Geese

80

*Violative samples

20 26,000

Source of Exposure

Tarpaper Fish viscera Ceiling insulation and fiberglass insulation with paper backing Contaminated fat added to feed during processing Fiberboard insulation and soil Transformer rupture onto soil and animals PCB-contaminated oil used as basis for topical pesticide Soil in junkyard

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distributed to three US feed processors and ultimately reached 19 states, Canada, and Japan before the incident was identified. 4 The contamination incident began with the identification of a PCBadulterated specimen from a Food Safety and Quality Service (FSQS) National Residue Program sample taken from Jolly Wholesale Poultry in Provo, Utah in early August, 1979. In September, two other chicken farms with PCB contamination were identified, intensifying concerns about the extent of contamination. After an intense investigation involving scores of agents from the FDA and the FSQS of the USDA and the testing of over 2500 samples, the source of the contamination was identified in mid-September as the hog slaughter plant. From mid-September through mid-November, investigators visited various establishments in an attempt to track the contaminated meat meal. As a result of this widespread contamination of animal feed, approximately 800,000 chickens, 3,840,000 eggs, 4000 hogs, 74,000 bakery items, 800,000 lb of animal feeds, and 1,200,000 lb of grease were destroyed. The estimated total cost of the recalls and destroyed foods cost private enterprises over $2 million. 3 Consequently, in January of 1980, a Contaminant Response System (CRS) was implemented to coordinate interagency collaboration during the investigation of future contamination incidents. Results of CRS investigations are listed in Table 3. DIOXINS

For purposes of this article, dioxins are defined as a family of about 30 compounds that have a similar chemical structure, have a common set of toxicologic properties, and include different congeners of polychlorinated dibenzo-p-dioxins (CDD), polychlorinated dibenzofurans (CDF), and polychlorinated biphenyls (PCB). There are 75 possible positional congeners of CDD, 135 different congeners of CDF, and 209 possible PCB congeners, but only about 30 of these 419 congeners have dioxinlike activity.39 After providing some background information on dioxins, this section focuses on the recent federal investigation that traced back the source of dioxins in broilers to a specific ingredient in their feed. Mechanism of Action and Effects

The 30 dioxin congeners appear to act by binding to the Ah receptor. They appear to produce in animals and humans a broad range of biochemical and morphologic changes. These changes include (1) a wasting syndrome, (2) immune suppression with effects on Band T cells, (3) species- and tissue-specific responses involving epithelial proliferation, altered differentiation, or both (e.g., chloracne in humans), (4) enhanced tumorogenicity as a result of tumor-promoting effects, (5) induction of enzymes such as cytochromes P4501A1, 1A2, and 1B, glutathione-S-transferase, and [tau]-aldehyde dehydrogenase by direct trans-

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Table 3. TABULATION OF PCB CRS REPORTS, 1989-1996 Animal Species

Slaughtered Lot

Violative

Steers and heifers

100

Y

Horse Market Hog Market Hog Geese Goat Sheep Heavy Calf Goat Boar

4-7 15 Unknown 225 Unknown Unknown Unknown Unknown 400

Y (1.99 ppm) N (0.35 ppm) N (1.81 ppm) N (1.30 ppm) N (2.16 ppm) Y (3.70 ppm) N (1.97 ppm) Y (15.90 ppm) Y (8.23 ppm)*

Veal Calf Horse Goat Sow Bull Mature Chickens

4 Unknown Unknown Unknown Unknown 26,000

N (1.64 ppm) Y (107.0 ppm) Y (10040 ppm) Y (4.70 ppm) N (1.0 ppm) N (0.14 ppm)

Boar Goat Goose Goose Horse Chicken

Unknown Unknown 200 80 Unknown 110,000

N N N N N N

(1.20 (2.56 (0.20 (0.20 (2.72 (1.79

ppm) ppm) ppm) ppm) ppm) ppm)

Source

Transformer shot, direct exposure to oil and soil Unknown Fish Viscera Unknown Unknown Unknown Unknown Unknown Unknown PCB-contaminated oil used as pesticide topical application Unknown Unknown Unknown Unknown Unknown Ceiling insulation, fiberglass insulation with paper backing Unknown Unknown Fiberboard insulation Soil in junk yard Unknown Contaminated fat in processed feed

*Applied

cription activation, and (6) many changes in other receptors and hormone levels (e.g., a decrease in the expression of the estrogen receptor).29

Human Exposure

The US Environmental Protection Agency (EPA) has the lead for the federal government in conducting a complete exposure and risk assessment for dioxins. The EPA has published nine draft volumes entitled Estimating Exposure to Dioxin-Like Compounds that provide detailed information on the exposure and risk assessment for dioxins. 38 Also, the Draft Toxicological Profile for Chlorinated Dibenzo-p-Dioxins 6 has a thorough discussion of the toxicologic data available for dioxins in humans and other animals. The draft EPA volumes and the draft Agency for Toxic Substances and Disease Registry (ATSDR) toxicologic profile both estimate that more than 90% of the dioxin exposures for humans in the United States is through the food supply.

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TCDD, TEQ, and TEF

The relative dioxinlike activity of various congeners is usually expressed in terms of 2,3,7,8-tetrachlorodibenzodioxin equivalents (TEQ). The 2,3,7,8-tetrachlorodibenzodioxin (TCDD) congener was selected as the reference compound for expressing dioxin equivalents because it is the most potent. Toxicity equivalency factors (TEF) were established for the various CDD and CDF congeners25, 26 and for the various PCB congeners 2 to promote international consistency in addressing dioxin contaminations. To convert analytic results to TEQ, multiply the analytic result (e.g., the concentration of each congener in parts per trillion) by the appropriate TEF. The sum of the TEQs from each of the 30 congeners provides the total TEQ for the sample. A list of the 30 congeners (and International Union of Pure and Applied Chemistry [IUPAC] No. for the PCBs) with their TEF is provided in Table 4 and are grouped in decreasing order of the TEF. Recent Federal Investigation of Dioxin in Food and Feed

In May of 1997, elevated levels of dioxins were found in 2 of 80 poultry samples (young chickens, young turkeys, heavy fowl, and light fowl) collected at slaughter in the recent USDA/EPA nationwide survey for dioxins in poultry.13 The two elevated samples were from two broiler chickens that were produced by one company, but one bird was slaughtered in Arkansas, and the other, in Texas. The dioxin levels in these samples tested above 3.5 ppt TEQ (as-is basis), whereas the average dioxin level in the other 78 poultry samples was about 0.14 ppt TEQ (as-is basis). The EPA also found similarly elevated dioxin levels in two additional broilers that they subsequently purchased from a supermarket in Louisiana. Trace-back of these two birds showed that they were produced by a different company from the joint USDA/EPA survey samples and were slaughtered at a plant in Arkansas. The two companies involved used different slaughter plants in Arkansas. Joint federal (FDA, USDA, EPA, and CDC) and state (Arkansas and Texas) investigations were conducted on poultry farms that produced the broilers with the elevated dioxin levels. On one farm, broiler feed, 12-day-old and 5-week-old broilers, and a number of environmental samples were collected. The results implicated the broiler feed as the likely source of the dioxins, because both the feed and the immature broilers showed elevated dioxin levels compared to the other on-farm samples. The dioxin congener pattern noted in the four broilers with elevated dioxin levels and the on-farm samples of broiler feed and immature broilers were all similar. The primary congener contributing to the total TEQ was TCDD, followed by 1,2,3,7,8-pentachlorodibenzodioxin (PeCDD)

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Table 4. A LIST OF THE 30 CONGENERS WITH DIOXIN-LIKE ACTIVITY AND THEIR TOXICITY EQUIVALENCY FACTORS Congener Name

Chlorinated Dibenzodioxins 2,3,7,8-tetrachlorodibenzodioxin (TCDD) 1,2,3,7,8-pentachlorodibenzodioxin (PeCDD) 1,2,3,4,7,8-hexachlorodibenzodioxin (4-HxCDD) 1,2,3,6,7,8-hexachlorodibenzodioxin (6-HxCDD) 1,2,3,7,8,9-hexachlorodibenzodioxin (9-HxCDD) l,2,3,4,6,7,8-heptachlorodibenzodioxin (HpCDD) octachlorodibenzodioxin (OCDD) Chlorinated Dibenzofurans 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) 2,3,7,8-tetrachlorodibenzofuran (TCDF) 1,2,3,4,7,8-hexachlorodibenzofuran (l,4-HxCDF) l,2,3,6,7,8-hexachlorodibenzofuran (1,6-HxCDF) 1,2,3,7,8,9-hexachlorodibenzofuran (1,9 HxCDF) 2,3,4,6,7,8-hexachlorodibenzofuran (4,6 HxCDF) l,2,3,7,8-pentachlorodibenzofuran (1-PeCDF) l,2,3,4,6,7,8-heptachlorodibenzofuran (1,4,6-HpCDF) l,2,3,4,7,8,9-heptachlorodibenzofuran (1,4,9-HpCDF) octachlorodibenzofuran (OCDF) Polychlorinated IUPAC No. PCB 126 PCB 169 PCB 77 PCB lS6 PCB 157 PCB 114 PCB lOS PCB 118 PCB 123 PCB 170 PCB 189 PCB 167 PCB 180

TEF

1 0.5* 0.1 0.1 0.1 0.01 0.001*

O.S 0.1 0.1 0.1 0.1 0.1 O.OS 0.01 0.01 0.001

Biphenyls 3,3',4,4',S-penta PCB 3,3',4,4',S,S'-hexa PCB 3,3' ,4,4' -tetra PCB 2,3,3',4,4',S-hexa PCB 2,3,3',4,4',S'-hexa PCB 2,3,4,4',S-penta PCB 2,3,3',4,4'-penta PCB 2,3' ,4,4' ,S-penta PCB 2',3,4,4',S-penta PCB 2,2',3,3',4,4',S-hepta PCB 2,3,3',4,4',S,5' -hepta PCB 2,3',4,4',5,S'-hexa PCB 2,2',3,4,4',S,5'-hepta PCB

0.1 0.01 O.OOOS 0.0005 0.0005 O.OOOS 0.0001 0.0001 0.0001 0.0001 0.0001 0.00001 0.00001

*The World Health Organization and others are considering changes in the TEFs noted. The TEF for PeCDD would be changed from 0.5 to 1; for OCDD, from 0.001 to 0.0001. The values in this article were calculated using the TEFs in the table above.

and 1,2,3,7,8,9-hexachlorodibenzodioxin (9-HxCDD). This pattern also resembled that of some of the catfish from the southeastern United States reported in Cooper et al (1996). Although the number of samples was quite limited in the Cooper catfish study, feed had been identified as the likely source of the dioxins in the catfish from Arkansas. Following investigation of the rations of the broilers and immature broilers, inspections and sampling at feed mills, contact with the authors of the catfish article, and a briefing on the dioxin investigation conducted by one of the affected broiler companies, the common link between the broilers and catfish appeared to be soybean meal produced by one

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company in Arkansas. Federal investigation of every process in the production of soybean meal at this manufacturing plant demonstrated that the dioxin contamination came from the use of ball clay as an anticaking agent for the soybean meal. The soybean oil was not contaminated, because the ball clay was added after extraction of the oil. The ball clay was added at approximately 0.3% to 0.5% of the soybean meal. Ball clay is currently listed in the Official Publication of the Association of American Feed Control Officials, Inc. as an anticaking agent and pelleting aid at levels not to exceed 2.5% in the finished feed. 1 The investigation then traced the ball clay back to its mine of origin. The company mining the ball clay stated that the clay came from a site in Mississippi and that it supplied ball clay for feed purposes to only two companies, both of which were soy processors in Arkansas. After analysis of the ball clay directly from the pit showed elevated levels of dioxins with a similar dioxin congener pattern, both soy processing companies and the supplier of the ball clay immediately stopped use of the ball clay for feed purposes and stopped the sale of any soybean meal on hand that contained the ball clay. A summary of the dioxin findings in the ball clay from the Mississippi mine, in the feed and immature broilers from the on-farm investigation in Arkansas, and in the catfish fillets from Cooper et al (1996) can be found in Table 5. The ball clay, feed, and immature broilers were analyzed for dioxins by the EPA lab in Stennis Space Center, Mississippi using EPA Method 1613.39 Although only a limited number of samples were analyzed, the feed-to-tissue ratio of the seven dioxin congeners in the broilers appears to decrease with increasing chlorination. The dioxin congener pattern (primary congener contributing to the total TEQ was TCDD, followed by PeCDD and 9-HxCDD) was used to establish the pathway of the elevated levels of dioxins through the food chain. The dioxin congener pattern in the ball clay from the Mississippi mine closely matched the pattern noted in the broiler feed and immature broilers from the on-farm investigation, in the catfish and catfish feed from Cooper et al (1996), and in eggs collected and analyzed by the FD A following a trace-back of the soybean meal through the food chain. The congener pattern in the two broilers from the USDA/EPA survey and the two subsequent EPA supermarket samples from Louisiana were also quite similar to that in the ball clay from the Mississippi mine. The CDF and PCB congeners were present at very low levels in these samples, if detected at all. Regulatory Action

After reviewing background levels of dioxins in catfish, eggs, and poultry, the FDA and USDA, in July of 1997, set an interim level of concern of 1 ppt TCDD in these commodities. This interim level of concern applied only to animals and animal products, like eggs and milk, where ball clay may have been used in their feed. The interim

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Table 5. TEO VALUES ppt FOR THE SEVEN CHLORINATED DIBENZODIOXIN CONGENERS IN BALL CLAY, BROILER FEED, AND BROILER TISSUES FROM THE MULTIAGENCY INVESTIGATION ARE COMPARED TO PREVIOUSLY PUBLISHED FINDINGS IN CATFISH Arkansas Poultry Producer 5-Week-Old Broilers COO Congener

Mississippi Mine Ball Clay*

Feedt

Tissuest

Catfish-

598.2 215.1 12.4 45.2 175.1 26.6 26.9

2.71 0.64 0.03 0.11 0.44 0.10 0.36

3.42 0.77 0.02 0.09 0.24 0.02 0.01

2.36 0.60 0.01 0.05 0.12 0.01 0.01

1,099.5

4.39

4.57

3.16

TCDD PeCDD 4-HxCDD 6-HxCDD 9-HxCDD HpCDD OCDD Total

*Average of three samples taken directly from the mining pit; TEQ values are expressed on an asis basis. tAverage of two starter feeds multiplied by 0.05 (fed for first 17-18 days) plus average of two finisher and two withdrawal feeds multiplied by 0.50 (fed since days 17-18); TEQ values are expressed on an as-fed basis-lipid-adjusted value multiplied by % fat (starter feeds were 5.6-6.1% fat, finisher feeds were 5.3%-6.0% fat, and withdrawal feeds were 6.5% fat). tAverage of two composites of four broilers; TEQ values are expressed on a whole-body basis-lipid-adjusted value multiplied by 0.15 . • Average of the two Arkansas catfish fillets from Cooper et aI, 1996; TEQ values are expressed on a whole-fillet basis-lipid-adjusted value multiplied by 0.08.

level was set at 1 ppt to distinguish between products from animals that had received the contaminated feed and those that did not. TCDD was selected as the marker residue because it was the primary congener present and to simplify the chemical analysis required. Food products (including fish, milk, eggs, and poultry) from animals that may have received some of the adulterated feed were sampled and either destroyed or cleared for use, or the animals were held for a depuration period on clean feed and sampled again. The 1 ppt TCCD level of concern is not a health-based safe level." No safe level, tolerance, or action level has yet been established for dioxins in animal feed, feed components, or food. Any future tolerance or action level for dioxins in animal feed, feed components, or food for humans may be above or below this level of concern. 1/

Ball Clays and Dioxins

Ball clays are often gray in color and are a mixture of clay minerals and nonclay impurities. Kaolinite is the dominant mineral present. Illite clay is the second most abundant clay mineral, and smectite and chlorite are present in minor amounts. The relative proportions of these minerals vary greatly. Quartz is the major nonclay mineral present, with minor

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HEADRICK et al

quantities of plagioclase, calcite, dolomite, and potassium feldspar reported. 27 In the United States, the major economic deposits are found in western Kentucky and Tennessee, in an arc including the northwestern corner of Mississippi. Owing to its plasticity, the primary use of ball clay is in the ceramic industry. Preliminary investigation of the Mississippi mine identified as the source of the contamination showed that dioxins were present throughout the deposit of ball clay, which was located approximately 50 ft below the surface. As there was no evidence of human-mediated contamination of the ball clay at this site, the possibility that the dioxins were deposited with the ball clay could not be ruled out. The investigation continued to other ball clay mines in the immediate area and to those mining the same geologic formation in neighboring states. It appears that the ball clay was deposited in old oxbow lakes and shallow marine lagoons in this geologic formation, the Mississippi embayment, and that these ball clay deposits were formed approximately 30 to 50 million years ago during the Eocene period. See Patterson and Murray27 for a discussion of ball clay and other related clays in North America. At this time, it is not known whether the geologic age or depositional environment for a particular type of clay is directly related to the dioxin congeners or concentrations found. Although only a limited number of samples have been analyzed to date, the preliminary evidence indicates that most, if not all, ball clays from mines in Mississippi, Kentucky, and Tennessee are likely to contain at least 400 ppt TEQ of dioxins. In comparison, the commonly observed range for dioxins in surface soil varies between rural and urban areas, but is approximately 1 to 20 ppt TEQ, respectively (John Schaum, EPA, personal communication). Once elevated dioxin levels were found in other ball clay mines, the FDA asked in July of 1997 that the ball clay not be used for food or feed purposes, and every company involved indicated that they would immediately comply with this request. On October 7, 1997, the FDA sent a formal letter to all producers or users of clay products in animal feeds conveying the same request. Whereas the TEQ was elevated from a limited sampling of the Tennessee and Kentucky ball clay mines, the CDD congener pattern differed from that of the Mississippi mine. The most abundant congeners were PeCDD and octachlorodibenzodioxin (OCDD), followed often by 9-HxCDD. TCDD comprised only 5% to 170/0 of the TEQ in these Tennessee and Kentucky ball clays, in comparison to more than 50% of the TEQ in the Mississippi mine. The predictability of dioxins in other materials called ball clay may be poor. For example, the FDA has preliminary evidence that materials called ball clay or fire clay from mines in Texas and Indiana may have normal background levels of dioxins. The FDA also has preliminary information that material called ball clay from a foreign country contains elevated dioxin levels. The FDA is reviewing the data submitted from the mines in Texas and Indiana and has requested further information about the ball clay in the foreign country. More information is needed

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129

to understand the pattern of dioxin deposition in clays, the causes for the high dioxin levels in many ball clay mines, and the apparent absence of dioxins from other clays. This multiagency investigation identified a previously unknown source of dioxins in ball clay; however, as is typical of new findings, there are several unanswered questions related to how the dioxins were deposited in the clay. The FDA is preparing a call for an informational document to be published in the Federal Register to try to answer these questions. The FDA will also be seeking information on the dioxin levels in other anticaking agents to prevent similar incidents in the future.

References 1. AAFCO: Official Publication 1998 of the Association of American Feed Control Officials Incorporated. Special Purpose Products, 1998, p 271 2. Ahlborg UG, et al: Toxic equivalency factors for dioxin-like PCBs: Report on a WHOECEH and IPCS consultation December 1993. Chemosphere 28(6):1049-1067, 1994 3. Anonymous: Report to the Chairman, Committee on Appropriations United States Senate; Further Federal Action Needed to Detect and Control Environmental Contamination of Food. Washington, DC: US General Accounting Office; 1980a. Publication CED-81-19 4. Anonymous: Report on the PCB Incident in the Western United States. Food Safety and Quality Service, US Department of Agriculture, Washington, D.C., 1980b 5. Anonymous: Scientific Advisory Panel on Brominated Biphenyls (PBB). Michigan Department of Public Health, Lansing, Michigan, 1976 6. ATSDR (Agency for Toxic Substances and Disease Registry): Draft Toxicological Profile for Chlorinated Dibenzo-p-Dioxins. Atlanta; ATSDR, Toxicology Information Branch, 1997 7. Battershill J: Review of the safety assessment of polychlorinated biphenyls (PCBs) with particular reference to reproductive toxicity. Hum Exp Toxicol 13:581, 1994 8. Boyer I, Kokoski C, Bolger P: Role of FDA in establishing tolerable levels for dioxin and PCBs in aquatic organisms. J Toxicol Environ Health 33:93, 1991 9. Cooper K, et al: PC DDs, PCDFs and PCBs in farm raised catfish from southeast United States. Organohalogen Compounds 28:197-202, 1996 10. Dewailly E, Ayotte P, Laliberte C: Polychlorinated biphenyl (PCB) and dichlorodiphenyl dichloroethylene (DOE) concentrations in the breast milk of women in Quebec. American Journal of Public Health 86:1241, 1996 11. Eyster J, Humphrey H, Kimbrough R: Partitioning of polybrominated biphenyls (PBBs) in serum, adipose tissue, breast milk, placenta, cord blood, biliary fluid, and feces. Arch Environ Health 38:1, 1983 12. Fries G: The PBB episode in Michigan: An overall appraisal. Crit Rev Toxicol 16:2, 1985 13. General Accounting Office: Food Safety Agencies' Handling of a Dioxin Incident Caused Hardships for Some Producers and Processors. Washington, DC: US General Accounting Office; 1998. Publication RCED-98-104, B-279328 14. Hall R: A new threat to public health: Organochlorines and food. Nutr Health 8:33, 1992 15. Halbert F, Halbert S: Bitter Harvest, The Investigation of the PBB Contamination: A Personal Story. Grand Rapids, Michigan, Wm B Eerdmans Publishing Co, 1978 16. Henck J, Mattsson J, Rezabek 0, et al: Developmental neurotoxicity of polybrominated biphenyls. Neurotoxicol Teratol 16:4, 1994 17. Henderson A, Rosen 0, Miller G, et al: Breast cancer among women exposed to polybrominated biphenyls. Epidemiology 6:5, 1995

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17a. Hogue A, Sigurdson A, Burau K, et al: Cancer among a Michigan cohort exposed to polybrominated biphenyls in 1973. Epidemiology 9(4):373-378, 1998 18. Jacobson J, Jacobson S: New Methodologies for Assessing the Effects of Prenatal Toxic Exposures in Cognitive Functioning in Humans. In Evans M (ed): Toxic Contaminants and Ecosystem Health: A Great Lakes Focus. John Wiley and Sons, New York, 1988, p 373 19. Jacobson J, Jacobson S: Intellectual impairment in children exposed to polychlorinated biphenyls in utero. N Engl J Med 335:783, 1996 20. Kamrin M, Fischer L: Workshop on human health impacts of halogenated biphenyls and related compounds. Environ Health Perspect 91:157-164, 1991 21. Landrigan P, Wilcox K, Silva J, et al: Cohort study of Michigan residents exposed to polybrominated biphenyls: Epidemiologic and immunologic findings. Annals New York Academy of Sciences (NYAS) 320:284-294, 1979 22. Lindstrom G, Hooper K, Petreas, et al: Workshop on perinatal exposure to dioxinlike compounds, I, Summary. Environ Health Perspect 103(suppl):135, 1995 23. Matsumura F: Mechanism of action of dioxin-type chemicals, pesticides and other xenobiotics affecting nutritional indexes. Am J Clin Nutr 61(suppl):695S, 1995 24. Mendola P, Buck G, Sever L, et al: Consumption of PCB-contaminated freshwater fish and shortened menstrual cycle length. Am J EpidemioI146:955, 1997 25. NATO/CCMS (North Atlantic Treaty Organization, Committee on the Challenges of Modem Society): International Toxicity Equivalency Factor (I-ECF) Method of Risk Assessment for Complex Mixtures of Dioxins and Related Compounds. 1988a. Report No. 176 26. NATO/CCMS (North Atlantic Treaty Organization, Committee on the Challenges of Modem Society): Scientific Basis for the Development of International Toxicity Equivalency (I-ECF) Factor Method of Risk Assessment for Complex Mixtures of Dioxins and Related Compounds. 1988a. Report No. 178 27. Patterson S, Murray H: Kaolin, refractory clay, ball clay, and halloysite in North America, Hawaii, and the Caribbean Region. Geological Survey Professional Paper 1306. Washington, DC: US Government Printing Office, 1984 28. Pijnenburg A, Everts J, de Boer J, et al: Polybrominated Biphenyl and Diphenylether Flame Retardants: Analysis, Toxicity, and Environmental Occurrence. In Reviews of Environmental Contamination and Toxicology, Springer-Verlag, New York, Vol 141. 1995 29. Poland AP: Studies on the mechanism of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin, CIIT Activities 16(5):4-6, 1996 30. Rogan W, Gladen B, McKinney J, et al: Neonatal effects of transplacental exposure to PCBs and DDE. J Pediatr 109:335, 1986a 31. Rogan W, Gladen B, McKinney J, et al: Polychlorinated biphenyls (PCBs) and dichlorodiphenyl dichloroethene (DDE) in human milk: Effects of maternal factors and previous lactation. American Journal of Public Health 76:172, 1986b 32. Rogan W, Gladen B, Hung K, et al: Congenital poisoning by polychlorinated biphenyls and their contaminants in Taiwan. Science 241:334, 1988 33. Rosen D, Flanders D, Friede A, et al: Half-life of polybrominated biphenyls in human sera. Environ Health Perspect 103:3, 1995 34. Schantz S, Jacobson S, Jacobson J, et al: Determinants of polychlorinated biphenyls (PCBs) in the sera of mothers and children from Michigan farms with PCB-contaminated silos. Arch Environ Health 49:452, 1994 35. Schecter A, Furst P, Furst C, et al: Levels of polychlorinated dibenzodioxins and dibenzofurans in cow's milk and in soy bean derived infant formulas sold in the United States and other countries. Chemosphere 19:913, 1989 36. Sherman J: Polybrominated biphenyl exposure and human cancer: Report of a case and public health implications. Toxicol Ind Health 7:3, 1991 37. Tacoma and Tacoma v Michigan Chemical Corporation: State of Michigan in the Circuit Court for the County of Wexford FDA-Detroit District Office, File No. 2933, October 26, 1978 38. US EPA: Estimating Exposure to Dioxin-like Compounds-Volume II: Properties, Sources, Occurrence and Background Exposures. US Environmental Protection

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39. 40. 41. 42. 43.

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Agency, Office of Research and Development; 1994. External Review Draft, EPA/ 600/6-88/005Cb, pp 1-1-2-4 US EPA, Telliard WA: EPA Method 1613: Tetra- through Octa- Chlorinated Dioxins and Furans by Isotope Dilution HRGC/HRMS. US Environmental Protection Agency, Office of Water; 1994. Publication EPA 821-B-94-005, Revision B Wolff M, Anderson H, Selikoff I: Human tissue burdens of halogenated aromatic chemicals in Michigan. JAMA 247:15, 1982 Wong 0, Brocker W, Davis H, et al: Mortality of workers potentially exposed to organic and inorganic brominated chemicals, DBCP, TRIS, PBB, and DDT. British Journal of Industrial Medicine 41:1, 1984 21 CFR 509.30 Temporary tolerances for polychlorinated biphenyls (PCBs) 21 CFR 109.30 Tolerances for polychlorinated biphenyls (PCBs)

Address reprint requests to Marcia 1. Headrick, DVM, MPH US Food and Drug Administration Center for Veterinary Medicine, HFV-218 7500 Standish Place Rockville, MD 20855