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Agency for Toxic Substances and Disease Registry
Polychlorinated Biphenyls (PCB) Toxicity
Physiologic Effects
- Adverse dermatologic, reproductive and developmental, endocrine, hepatic, and immunologic effects have been associated with exposure to PCBs.
Evidence on the physiologic effects of exposure to PCBs has been obtained from
- studies of industrial workers exposed to PCB-containing mixtures in the course of their work,
- two episodes of mass poisoning that occurred in Japan (the 1968 Yusho incident) and Taiwan (the 1979 Yu-Cheng incident), and
- studies of adults and children exposed to PCBs as a result of consuming contaminated sport fish.
In the two Asian episodes, exposure to PCBs occurred via the consumption of rice oil that had become contaminated by heat-degraded PCBs during processing. Unlike usual PCB mixtures, the Yusho and Yu-Cheng mixtures were heated in thermal heat exchangers during the cooking process, resulting in contamination of the oil by chlorinated dibenzofurans as well as PCBs. This co-contamination created controversy about the extent to which the physiologic effects observed in the Yusho and Yu-Cheng populations can legitimately be attributed to PCBs, as opposed to the dibenzofuran co-contaminants.
- PCB-induced chloracne can be a sign of systemic toxicity.
Chloracne is the only overt effect of PCB exposure in humans. In a person with PCB-induced chloracne, the acneform lesions arise as a result of inflammatory responses to irritants in the sebaceous glands. Chloracne usually begins with the formation of keratin plugs in the pilosebaceous orifices. The resulting inflammatory folliculitis stimulates keratinization of the sebaceous gland ducts and outer root sheath of the hair, leading to the formation of keratin cysts (ATSDR 2000a).
The chin, periorbital, and malar areas are most often involved, although lesions might also appear in areas not usually affected by acne vulgaris (e.g., the chest, arms, thighs, genitalia, and buttocks). The most distinctive lesions are cystic and measure from 1 to 10 mm, although comedonal lesions can also be present. The cysts and comedones can become inflamed and secondarily infected, and papules and cysts can be surrounded by edema and erythema.
Chloracne generally indicates systemic toxicity and can result not only from dermal contact but also from ingestion of PCBs. However, the absence of chloracne does not rule out exposure. No reliable dose-response model exists for chloracne in exposed populations, and the dose-response relationship might be dependent on individual predisposition. Chloracne typically develops weeks or months after exposure. The lesions are often refractory to treatment and can last for years to decades.
In addition to chloracne, persons in the Yusho population had hyperpigmentation of the skin, conjunctivae, gingivae, and nails. These pigmentation disturbances have also been noted in some PCB-exposed workers.
- Reproductive function can be disrupted by exposure to PCBs, although more research is required to assess this possibility.
Recent studies indicate that consumption of PCB-contaminated fish can cause disturbances in reproductive parameters and cause neurobehavioral and developmental deficits in newborns and older children. Prenatal exposure to PCBs from the mothers body burden, rather than exposure through human milk, is believed to account for the developmental effects of these compounds (AAP 1999).
In rhesus monkeys, exposure to PCBs is associated with alterations in the menstrual cycle, decreases in fertility, increases in spontaneous abortion, and a reduced number of conceptions (ATSDR and EPA 1998). Some of these effects have also been reported in human populations. In a study of 626 married couples in Michigan, the relative risk of conception failure (defined as an inability to conceive after 12 months) increased in men but not in women with increasing consumption of PCB-contaminated fish. Some evidence shows that menstrual cycle length can be reduced with increased PCB intake, but no adverse association was found between the duration of fish consumption and time-to-pregnancy in the same population. In a study of 1,820 multigravada women, no significant association was found between low to moderate PCB intake and clinically recognized spontaneous fetal death (ATSDR and EPA 1998).
- Neurobehavioral and developmental deficits have been reported in newborns exposed to PCBs in utero, and these deficits continue in school-aged children.
The first epidemiologic investigation to demonstrate an association between the amounts of PCB-contaminated fish eaten by pregnant women and behavioral deficits in their newborns was the Michigan Maternal Infant Cohort Study, published in 1984 (ATSDR and EPA 1998). In this study, developmental and cognitive deficits were observed in the children of mothers who had eaten moderate to high amounts of contaminated fish during the 6 years preceding pregnancy and who continued to do so during pregnancy. Developmental effects in this population included statistically significant decreases in gestational age (4.9 days), birth weight (160190 g), and head circumference (0.6 cm); neurobehavioral deficits included depressed responsiveness, impaired visual recognition, and poor short-term memory. In addition, the infants born to mothers who had eaten the greatest amount of contaminated fish during pregnancy exhibited weaker reflexes, greater motor immaturity, and more pronounced startle responses than infants born to women who had consumed less fish (ATSDR and EPA 1998). Women in their childbearing years must be aware of fish advisories.
Follow-up studies of the children from this cohort have demonstrated that the effects of perinatal exposure to PCBs are persistent. At 4 years of age, these children still had deficits in weight gain, depressed responsiveness, and reduced performance on the visual recognition-memory test. At 11 years of age, the children of highly exposed mothers were three times more likely than controls to have low full-scale verbal IQ scores, were twice as likely to lag behind at least 2 years in reading comprehension, and were more likely to have difficulty paying attention (ATSDR and EPA 1998).
Similar developmental and neurobehavioral deficits have been reported in children born to women who were pregnant during the Yusho and Yu-Cheng incidents. Developmental delays were seen at all ages and were greater in children who were smaller in size, had neonatal signs of intoxication, and/or had a history of nail deformities. Follow-up testing indicated that effects on cognitive development persisted for several years after exposure (ATSDR and EPA 1998).
- PCBs can mimic or disrupt the action of thyroid and/or female sex hormones.
PCBs have been identified as possible environmental endocrine modulators (chemicals that mimic or disrupt the action of naturally occurring hormones) (ATSDR 2000a). The best understood effects of PCB exposure on endocrine function involve disturbances in processes normally mediated by thyroid and female sex hormones.
The thyroid gland is an unequivocal target of PCBs in rats, and limited but corroborative occupational data indicate a potential for thyroidotoxic effects in humans (ATSDR 2000a). In a Dutch population, elevated PCB levels correlated with lower maternal levels of circulating triiodothyronine and total thyroxine and with higher plasma levels of thyroid-stimulating hormone in infants during the second week and third month after birth. Infants exposed to higher levels of PCBs also had lower plasma levels of free thyroxine and total thyroxine in the second week after birth (ATSDR and EPA 1998). In another study, hypotonia at birth was related to prenatal PCB exposure in infants who also exhibited elevated levels of thyrotropin (AAP 1999).
Because thyroid hormones are essential for normal behavioral, intellectual, and neurologic development, it is possible that the deficits in learning, memory, and attentional processes observed in the offspring of PCB-exposed women are partially or predominantly mediated by alterations in hormonal binding to the thyroid hormone receptor (ATSDR and EPA 1998). Some PCB congeners are capable of competing with endogenous hormone for binding to this receptor (AAP 1999), suggesting a possible mechanism of thyroidotoxicity. Hydroxylated PCB metabolites appear to be particularly potent in this regard (ATSDR 2000a).
Other subsets of PCB congeners might interfere with the biological effects of estrogen. Depending on the spatial orientation of their chlorine constituents, some congeners exhibit weak estrogenic activity, whereas others act as antiestrogens (ATSDR 2000a). The implications of this activity for human health are not well understood. In the Taiwanese Yu-Cheng population, adolescent males who had been exposed to high PCB levels in utero progressed normally through the Tanner stages but had smaller penises than did controls (AAP 1999). Girls who were similarly exposed exhibited a growth delay but otherwise normal development at puberty. It is not known, however, whether either of these effects was estrogenic (AAP 1999).
- Although liver damage is common in PCB-exposed animals, overt hepatotoxicity is uncommon in humans.
Histologically documented liver damage is a consistent and prominent finding among PCB-exposed animals; however, no evidence of hepatic dysfunction or overt hepatotoxicity has been seen in PCB-exposed workers (ATSDR 2000a). In the Yu-Cheng population, the incidence of chronic liver disease and cirrhosis was significantly higher than the incidence of these conditions in the general population of Taiwan (ATSDR and EPA 1998). Asymptomatic hepatomegaly has been reported in exposed workers, many of whom had concomitant elevated serum PCB levels.
Strong evidence shows that exposure to PCBs can increase serum liver enzyme levels. Some researchers believe that aspartate aminotransferase (SGOT or AST) and gamma glutamyl transpeptidase (GGTP or GGT) are the most sensitive indicators of PCB exposure in humans, and that changes in these enzymes can occur at exposure levels below those at which chloracne appears.
- Exposure to PCBs can increase serum levels of hepatic enzymes and can induce microsomal enzyme function.
Increases in urinary porphyrin levels were noted in a study of workers with low-level PCB exposure, an effect that is believed to be secondary to the induction of hepatic microsomal enzymes. Total bilirubin levels exhibit a positive correlation, and serum albumin a negative correlation, with serum PCB levels (ATSDR and EPA 1998). The reported effects of PCB exposure on serum triglycerides and cholesterol have been inconsistent, and are probably related to the partitioning effects of PCBs. Those correlations that have been reported do not appear to be of toxicologic significance because they were observed in persons with normal lipid levels (ATSDR 2000a). In animal studies, reductions in the hepatic storage capacity for vitamin A have also been reported (ATSDR 2000a), but the implications of this finding for human health are not known.
Microsomal enzyme induction by PCBs has been observed in the liver of humans and in extrahepatic tissues of animals (ATSDR 2000a). Different PCB mixtures may induce a variety of the CYP (P450) family of enzymes. The set of enzymes induced depends on the particular PCBs in the mixture; sometimes the induced enzymes are similar to those induced by Phenobarbital, other times different distinctive sets of enzymes are induced, and sometimes there is no enzyme induction. Enzyme induction may affect how rapidly both endogenous (e.g. hormones) or exogenous substances (drugs, environmental metabolites, etc.) are metabolized.
- On the basis of results from high-dose animal studies, PCBs are considered probable human carcinogens (Group 2A classification, International Agency for Research on Cancer).
The results of epidemiologic studies have raised concerns about the potential carcinogenicity of PCBs. In studies of occupationally exposed workers, increases in the incidence of malignant melanoma and cancers of the liver, gall bladder, biliary tract, and brain have been reported. In persons without known occupational exposure to PCBs, elevations in the serum PCB level have been associated with an increased risk of non-Hodgkin lymphoma (ATSDR and EPA 1998). Because of their estrogenic properties, PCBs have also been proposed as possible inducers of breast cancer; however, the results of epidemiologic studies in PCB-exposed women have been inconsistent (ATSDR 2000a).
At present, the weight of evidence from human studies does not support a causal association between PCBs and human cancer (ATSDR 2000a). Limitations in the design of these studies and the inconsistency of results rom one population to another make it difficult to ascertain whether the observed effects were causally related to PCB exposure. However, data from animal studies have clearly shown that PCBs cause hepatocarcinomas, pituitary tumors, leukemia, lymphomas, and gastrointestinal tract tumors. On the basis of these data, EPA considers PCBs a probable human carcinogen.
- Additional adverse effects of PCBs involve the neurologic, cardiovascular, immune, musculoskeletal, and gastrointestinal systems.
Occupational and epidemiologic studies have suggested or demonstrated other adverse health effects from exposure to PCBs, including effects involving the neurologic, cardiovascular, immune, musculoskeletal, and gastrointestinal systems.
In southwest Quebec, adults who ate fish from PCB-contaminated waters had significantly greater motor retardation, poorer results on certain tests of memory and attention, and higher scores on a standardized confusion scale than did controls, and these neurologic deficits were directly related to the frequency of fish consumption (ATSDR and EPA 1998).
In a study of persons living near a hazardous waste site, the incidence of borderline and definite hypertension was 30% greater among PCB-exposed persons than among controls, and the increases in blood pressure were significantly associated with serum PCB levels (ATSDR and EPA 1998). However, the existing data are insufficient to infer possible cardiovascular toxicity of PCBs in humans (ATSDR 2000a).
Immune system effects reported in PCB-exposed populations have included decreases in natural killer cell count, decreases in IgA and IgM antibody levels, alterations in the ratio of helper to killer (CD4+/CD8+) T-cells, and decreases in monocyte and granulocyte counts. In the Yusho and Yu-Cheng populations, the immunosuppressive effects of PCB exposure were associated with an increased incidence of persistent respiratory infection and enhanced responsiveness to mitogens (ATSDR and EPA 1998).
Joint pain occurs in 11% of workers exposed to PCB-containing mixtures (ATSDR 2000a). This rate is similar to the 10% incidence of unspecified joint pain reported in farm families who consumed beef and dairy products contaminated with PCBs (ATSDR and EPA 1998). However, the cause of joint pain and its association with PCB exposure remain uncertain.
Appetite loss has been reported in transformer and electrical equipment manufacturing workers exposed to various PCB-containing mixtures (ATSDR and EPA 1998). Other nonspecific gastrointestinal symptoms experienced by workers exposed to PCBs include nausea, epigastric distress and pain, and intolerance to fatty foods (ATSDR 2000a).
| 4. |
Is there a need to be concerned about PCB exposure when the clinical effects in this patient seem so limited? |
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