THE MERCK VETERINARY MANUAL
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Overview of Persistent Halogenated Aromatic Poisoning

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Persistent halogenated hydrocarbons (PHAs) are manmade chemicals and can be products of incomplete combustion. PHAs are a complex mixture of chemicals with differing molecular composition. Some PHAs are added to consumer products to provide unique properties and have been/are used as pesticides and disinfection agents. Most PHAs persist in the environment and are classified as persistent organic pollutants. PHAs cause acute and chronic toxicity. There is evidence that lifetime chronic toxicity can be expressed differently during life stages from embryogenesis to senility. Exposure at early life stages may not be expressed until a later life stage. PHAs can be biomagnified in body fat and liver, translocated to the fetus, and secreted in milk and eggs. Biomagnification is a process wherein PHAs are concentrated in fat and liver at a factor higher than dietary levels and is a food safety issue. Important groups of PHAs include polybrominated diphenyl ethers (PBDEs), polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), DDT, and triclosan.

Exposure to PHAs results from contamination of the indoor environment, especially house dust, atmospheric deposition of PHAs, amending agricultural lands with sewage sludge and industrial wastes, industrial incidents, and feed contamination including byproduct ingredients. Indoor dust is an important route of exposure of companion animals to PBDE fire retardants. For the other PHAs, diet is generally considered the primary route of exposure. Atmospheric PHAs, dispersed worldwide, tend to have higher concentrations in the arctic and antarctic regions. Atmospheric PHAs are deposited on soil and forages. Consumption of contaminated forage and soil by ruminants is a significant source of PCDD/Fs and other PHAs in the food web. Animal byproducts containing PHAs, previously biomagnified in fat and liver by other animals in the food web, are also an important source of PHAs in animal diets. Ball clay contaminated with PCDDs has been incorporated in the diets of food-producing animals, and contaminated clay has been used in human food processing. Exposure assessments must include all sources of PHAs. Human dietary exposure to PHAs is generally from ingestion of ruminant products and farmed and wild fish. Cats, like small children, are also exposed in the indoor environment.

Soil can be contaminated by industrial activity and spreading of waste materials on land. For example, spreading sewage sludge on soil can cause a 50× increase in the soil levels of PCDDs. Levels of PBDEs in sewage sludge have been reported as high as 2.3 ppm (dry), and the most consistent PBDE in sewage sludge is the penta-PDE. The primary source of the PCDD/Fs in forages harvested from contaminated soils is incorporated soil. Grass silages generally contain more PCDD/Fs than corn (maize) silage. The congener profile in forages can be used to chemically "fingerprint" the sources. Birds and other animals consume soil by geophagy when feeding. Grazing cattle and sheep can consume up to 17% and 30%, respectively, of the dry matter intake as soil. Ruminants and horses can also be exposed to PHAs by direct atmospheric deposition on vegetation. Atmospheric levels of PHAs generally vary with the season.

Companion animals have indoor environmental exposures to PHAs, especially the PBDEs, and cats are studied as a model to assess infant/toddler exposure. The PBDEs are a chemical mixture of congeners solubilized in plastics, carpets and other synthetic fabrics and foams, and electronic equipment to retard combustion. They contaminate indoor air as a vapor, migrate from carpets and other synthetic fibers, and are a component of house dust. PBDEs can also leach from products after disposal. The PBDEs with a lower bromination number generally are more environmentally persistent in food webs. The higher brominated PBDEs can be debrominated by biota to lower brominated PBDEs. Burning plastics containing PBDEs forms polybrominated dibenzo-p-dioxins (PBDDs) and dibenzofurans (PBDFs). The PBDD/Fs have toxicity similar to that of their chlorinated analogs and have been measured in adipose tissue. Triclosan, a polychlorinated hydroxydiphenyl ether, is widely used as broad-spectrum bactericide and is an ingredient in many cleaning agents and hygiene products. Surfaces of products such as cutting boards, food wrappers, refrigerator linings, and cat litter can be impregnated with triclosan for bacteriocidal action and to reduce odors. PHAs can be present in feedstuffs fed to dogs and cats. For example, fish oil, which may be used in formulated diets, generally is 2-fold higher in PCDD/Fs than in meat and bone meal.

PHAs are readily absorbed from the gut, lungs, and through the skin. After absorption, they can be biomagnified in body fat and the liver, translocated to the fetus, and excreted in milk and eggs. Food-producing animals can relay PHAs in foods and animal byproducts. PHAs are in rendered animal products, including fat, bone, and meat meals. After absorption, the congener profile can be altered by biotransformation, with the congener profile in tissues and edible animal products different from the PHAs absorbed. The congeners translocated to the fetus can be different from the congeners deposited in fat. Toxicity can vary with the congener profile. Biomagnification of PHAs has been estimated for chickens and pigs. PHAs analyzed in chicken fat had biomagnification factors ranging from 7 to 35. For pigs, biomagnification factors ranging from <7 to 15 were observed. Lactating and egg-laying females generally have a lower body burden of PHAs. The PHA levels in milk generally are higher during the early part of the first lactation. In rainbow trout, ~30% of the dietary PCDD/Fs are transferred to fat located in muscle tissue. The biomagnification factor generally varies between PHAs, animal species, and food webs.

Studies have shown that people and domestic and wild animals are exposed to a chemical soup of PHAs throughout a lifetime. The possible antagonistic, additive, synergistic, and potentiating interactions of the PHAs in the mixture are not well known.

PHA groups and individual PHAs are potent up- and down-regulators of enzyme systems by interaction with immunotoxic nuclear receptors; some PHAs interact with an assortment of endocrine receptors. Cell signaling can also be disrupted. Exposure begins during embryologic development and continues with possible differing toxic effects occurring during development, maturation, and aging. For some effects, toxicity occurring at one life stage may not be expressed until the next life stage. The general toxicology includes disruption of the immune and endocrine systems and associated organs/functions. Immunotoxicity is considered a sensitive parameter for some PCBs and TCDD/Fs congeners. The overall immune effect is reduced native resistance to infectious disease and a likely increased risk of neoplasia. The best-studied immunotoxic effect of PHAs is on the lymphocytes and acquired immunity. An abnormal increase in occurrences of infectious diseases can be observed in affected animals.

PHAs can alter endocrine functions. The US National Toxicology Program Workshop Review concluded there is evidence to support an association between selected exposure to PHAs and type 2 diabetes in people. Studies suggest that some PHAs may act as obesogens. There is growing general consensus that increased diagnosis of obesity in companion animals cannot be fully explained by genetics, lifestyle, and nutrition. Cats with lower capacity to metabolize PCBs have increased risk of acromegaly. In cats, an association between diabetes and PHA exposure has not been demonstrated in the studies published. Some PHAs are known to have an effect on thyroid endocrinology. The PHAs that induce hepatic uridine diphospho-glucuronosyltransferase or sulfotransferase isozymes increase biliary excretion of conjugated thyroid hormones. Some PCBs or their metabolites may interfere with binding of thyroid hormones to transporter proteins and the nuclear receptor. Exposure in utero to PCBs can increase brain deiodinases and may be a compensatory response to maintain tissue T3 concentrations due to decreased fetal circulating and brain concentrations of T4. There is an association between high levels of PBDEs in house dust and hyperthyroidism in cats. Blood levels of PHAs have not been associated with hyperthyroidism in cats. The PBDEs have been shown in laboratory studies to disrupt thyroid function in mice and American kestrels. One mechanism appears to be competitive displacement of T4 from its carrier protein by hydroxylated PBDE metabolites. Tetrabromobisphenol A has been shown to alter the thyroid hormone receptor. There is evidence that triclosan disrupts thyroid function.

PHAs can be steroid hormonal agonists and antagonists and can disrupt endocrine homeostasis. These disruptions can cause reproductive dysfunctions. A study on PCBs in cattle tissues showed that the stimulatory effects of follicle-stimulating hormone and luteinizing hormone on luteal, granulosa, and thecal cells were decreased for secretion of progesterone, estradiol, and testosterone, respectively. Using cattle uterine strips, PCBs have been shown to increase the force of myometrial contractions and increase endometrial section of prostaglandin F2α. Exposure to PCBs and brominated biphenyls can delay onset of parturition in cattle.

There is increasing concern that some PHAs can alter hormonal function in utero. Exposure to PHAs in utero may alter body mass index and sexual functions later in life. Pre- and postnatal exposure to PHAs, through endocrine disruption mechanisms, may alter mammary gland development and function and increase the risk of mammary diseases. Goats exposed to PCBs in utero had altered adenyl function that varied with age and sex. The goats had lower basal cortisol levels during prepubertal development, and this effect persisted during their first breeding season. Male goats at 9 mo of age had a greater and prolonged rise in plasma cortisol levels when subjected to moderate stress.

PHAs can up-regulate the activities of cytochrome CYP (P450) and other enzymes. Changes in drug metabolism can occur. Changes in CYP activity can increase the formation of the ultimate toxicant of a variety of toxic substances. PHAs can also be promoters of carcinogens.

In chickens, acute exposure to PHAs may cause a sudden drop in egg production followed by reduced egg hatchability. Ascites and edema may be seen, together with ataxia. Lesions include degenerative changes in skeletal and cardiac muscle. Altered thyroid function is associated with anomalous development in birds and mammals.

In cats, acromegaly appears to be linked to a decreased ability to metabolize PCB congeners. Hyperthyroidism in cats is associated with high levels of PBDEs in house dust. Feeding mink or whale blubber, naturally contaminated with PHAs and other pollutants, to sled dogs was shown to increase occurrences of diffuse thickening of the glomerular capillary wall and Bowman's basement membranes. Tubular hyalinization-degeneration and increased chronic interstitial nephritis were also noted.

Blood, plasma, serum, body fat, and liver can be assayed for PHAs. These levels can be linked to exposure and clinical and pathologic findings to establish a putative diagnosis.

There is no known treatment for intoxication by PHAs. Supportive care is recommended. Attention should be given to the indoor environment, the use of nonplastic feeding and watering utensils, and feed sources to prevent exposures to PBDEs. Avoiding contact with materials impregnated with PBDEs reduces the percutaneous exposure of companion animals. Avoiding household furnishings and plastics that contain PBDEs generally reduce the levels of PBDEs in the indoor environment. Allowing a companion animal more access to the outdoors reduces the indoor exposure to PBDEs. The PHAs in body fat are excreted in milk fat and contribute to the body burden of the neonate. The levels in milk are higher in the first lactation.

Last full review/revision February 2014 by Robert W. Coppock, DVM, MS, PhD, DABVT, DABT

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