PCBs and Dioxins

PCBs and Dioxins HESTIEN J. I. VREUGDENHIL AND NYNKE WEISGLAS‐KUPERUS DEPARTMENT OF PEDIATRICS DIVISION OF NEONATOLOGY, ERASMUS MC–SOPHIA CHILDREN’S HOSPITAL UNIVERSITY MEDICAL CENTER, ROTTERDAM, THE NETHERLANDS

I. A.

NEUROTOXICOLOGY OF PCBs AND DIOXINS

Chemical Properties and Deposition

PCBs and polychlorinated dibenzo‐para‐dioxins (PCDDs) and polychlorinated dibenzo‐furans (PCDFs) (the latter two are summarized as dioxins) are polyhalogenated aromatic hydrocarbons with comparable molecular structures. They consist of a biphenyl ring and, depending on the number and position of chlorine atoms on the two rings, there are 209 theoretically possible PCB discrete chemical compounds, called congeners, and 210 diVerent dioxin congeners (75 PCDDs and 135 PCDFs). Their basic structure is presented in Fig. 1. PCBs were commercially produced as complex mixtures (under trade names such as Aroclor, Clophen, Phenoclor) for a variety of applications, such as dielectric fluids for capacitors and transformers, heat transfer fluids, hydraulic fluids, lubricating and cutting oils, and as additives in pesticides, paints, adhesives, sealants, carbonless copy paper, flame retardants, organic dilutents, and plastics. Their commercial utility was based largely on their chemical and physical stability, including low flammability and their miscibility with organic compounds. The total amount of PCBs produced worldwide from 1929 to the 1980s, when most countries reduced or stopped the production, has been estimated at approximately 1.5 million metric tons (de Voogt & Brinkman, 1989; WHO, 1989). In 1982, it was estimated that 31% had been released to the environment and 65% was still in use or in storage, or deposited in landfills (Tanabe, 1988). Moreover, PCBs can be formed unintentionally as by-products in a variety of chemical processes that contain chlorine and hydrocarbon sources. Dioxins are generally formed as unwanted and often unavoidable byproducts during the synthesis of a wide array of commercial chemical INTERNATIONAL REVIEW OF RESEARCH IN MENTAL RETARDATION, Vol. 30 0074-7750/06 $35.00

47

Copyright 2006, Elsevier Inc. All rights reserved. DOI: 10.1016/S0074-7750(05)30002-4

48

Hestien J. I. Vreugdenhil and Nynke Weisglas-Kuperus

FIG. 1. Molecular structures of PCBs, PCDDs, and PCDFs.

products, especially those based on chlorinated aromatics, precursors, and intermediates. Moreover, they are formed during various combustion processes, such as burning of solid waste from municipal incinerators. B.

Toxic Mechanisms

The first mechanism that was described for toxic eVects of PCBs and dioxins was, after entering cells, their interaction with a cytoplasmic receptor protein, the aryl‐hydrocarbon (Ah) receptor (Safe & Goldstein, 1989). Depending on the positions of the chlorine atoms on the biphenyl ring

PCBS AND DIOXINS

49

structure (ortho, meta, or para position), and consequently the planar shape, the diVerent compounds bind, to a certain extent, to this receptor. Dioxins as well as dioxin-like PCBs (coplanar PCBs; having no chlorine atom on the ortho position) are recognized as potent compounds to interact with the Ah receptor (Safe, 1994). Furthermore, two other groups of PCBs can be distinguished based on the ability to interact with the Ah receptor, mono‐ ortho‐substituted PCBs (weak dioxin-like) and ortho‐substituted PCBs (nondioxin-like PCBs). Mono‐ortho‐substituted congeners have one chlorine atom on the ortho position and are intermediate in their ability to interact with Ah receptors. Ortho‐substituted have more than one ortho‐substitution on the biphenyl ring, which reduces the planarity of the molecule and reduces the ability to interact with the Ah receptor (Kafafi et al., 1993). Both non‐ortho‐substituted (coplanar compounds) and ortho‐substituted PCBs are toxic. Their mechanism of toxicity, however, is likely to be diVerent. As described previously, toxicity of coplanar compounds appears to be mediated by the Ah receptor (Safe, 1994). The toxic potency of a coplanar PCB congener is reflected in a toxic equivalent factor (TEF), based on its ability to bind the Ah receptor relative to the binding ability of the most potent dioxin, TCDD (Safe, 1990; Van den Berg et al., 1998a). For noncoplanar PCBs, the ability of the TEF to predict their neurotoxic potency is low (Giesy & Kannan, 1998; Shain et al., 1991). Since 1995, there is growing evidence that especially non-dioxin-like PCBs and weak dioxin-like PCBs and their metabolites, such as hydroxylated PCBs, may produce a wide spectrum of neurotoxic eVects, while dioxin-like PCBs may have less activity in the central nervous system (CNS) (Fischer et al., 1998; Korach et al., 1988; Shain et al., 1991). C.

CNS Effects

Neurochemical studies have shown that many elements of the CNS, and especially of the developing CNS, are susceptible to exposure to PCBs and dioxins, including cellular and synaptic processes and endocrine systems (Brouwer et al., 1995, 1999; Mariussen & Fonnum, 2001; Tilson & Kodavanti, 1998). These aspects will be further discussed in the following text. At the cellular level, PCBs‐induced alteration in markers for neuronal and glial cell development have been reported in several brain areas in rats that were perinatally exposed to a PCB mixture (Morse et al., 1996a). The levels of these markers for structural and functional brain development were altered in a complex manner, depending on age, sex, or brain region of the animal. The changes were suggestive of neuronal damage or death and were reported in several areas of the brain, including the lateral olfactory tract, striatum, prefrontal cortex, and in the cerebellum and brain stem (Morse et al., 1996a). Perturbations were also reported on intracellular calcium

50

Hestien J. I. Vreugdenhil and Nynke Weisglas-Kuperus

homeostatic mechanisms and second messenger systems that play a role in neuronal growth and normal physiology of cells (Kodavanti & Tilson, 1997; Kodavanti et al., 1993, 1994; Shafer et al., 1996). EVects of exposure to PCBs on synaptic processes included an inhibition of the synaptic transmission assessed in the dendate gyrus of the cerebral cortex in adult rats (Gilbert & Crowley, 1997) as well as in the hippocampus (Niemi et al., 1998) and in the visual cortex in prenatally exposed rats (Altmann et al., 1995). Synaptic transmission can be measured by means of long‐term potentiation, which is a model of synaptic plasticity that is suggested to be related to learning and memory at the synaptic level (McNaughton, 1993). Several brain neurotransmitter systems have been shown to be aVected by exposure to PCBs and dioxin, including dopamine, serotonine, glutamate, GABA, and cholinergic systems (Eriksson et al., 1991; Mariussen & Fonnum, 2001; Mariussen et al., 1999; Morse et al., 1996b; Seegal et al., 1997). EVects of perinatal exposure on dopaminergic systems have been documented most thoroughly. It appeared that in rats, developmental exposure to PCBs can result in opposite alterations in brain dopamine concentrations, depending on the type of the congener. For example, perinatal exposure to ortho‐substituted PCBs led to decreases in brain dopamine, whereas perinatal exposure to a coplanar PCB congener resulted in elevated concentrations of dopamine (Brouwer et al., 1995; Seegal et al., 1997). D.

Other Toxic Effects

PCBs and dioxins, and especially one type of PCB metabolites, the hydroxylated PCB metabolites, are presently known as endocrine disrupters. Multiple PCB congeners may impact upon multiple endocrine systems that may communicate with each other and are involved in fetal CNS development. These complex mechanisms of actions have not been much studied, and their role in developmental neurotoxic PCB and dioxin eVects remains largely unknown. Most information is available on thyroid hormone changes, generally including decreases in plasma thyroid hormone levels in fetal and neonatal rats as well as in plasma of the women of the Dutch cohort and their children, 2 weeks after birth (Brouwer et al., 1995, 1998; Koopman‐Esseboom et al., 1994b). Moreover, interactions with the steroid hormone system are suggested, due to PCB‐ and dioxin‐induced changes in steroid hormone homeostasis or to endocrine-like actions of these contaminants, particularly during development (Golden et al., 1998). Estrogenic (Bitman & Cecil, 1970; Kester et al., 2000; Korach et al., 1988), anti‐estrogenic (Amin et al., 2000; Jansen et al., 1993; Kramer et al., 1997; Moore et al., 1997), and anti‐androgenic (Hany et al., 1999) eVects have been

PCBS AND DIOXINS

51

described in in vivo and in vitro studies, possibly depending on congener type and/or metabolite.

II.

HUMAN EXPOSURE TO PCBs AND DIOXINS

Ninety percent of human exposure to PCBs and dioxins occurs through the diet, with food of animal origin being the predominant source (i.e., background exposure) (Furst et al., 1992). Contamination of food is primarily caused by deposition of emissions of various sources on farmland and water (waste incineration, production of chemicals) followed by bioaccumulation in the food chains, in which they are particularly aYliated with fat. Other sources may include contaminated feed for cattle, chicken, and farmed fish, improper application of sewage sludge, flooding of pastures, and waste eZuents (Furst et al., 1992). Since PCBs and dioxins are lipid‐soluble and are only slowly degraded, with half‐lifetimes in humans ranging from 1.8 to 9.9 years (Steele et al., 1986; Taylor & Lawrence, 1992), these compounds accumulate in adipose tissue. During pregnancy, PCBs and dioxins are transferred through the placenta and are able to cross the blood–brain barrier, exposing the fetus during a vulnerable time of CNS development (Masuda et al., 1978). PCBs have been detected in brain tissue of stillborn babies, exposed to environmental levels of PCBs, from 17 weeks of gestational age onward (Lanting et al., 1998a). A breast‐fed infant is additionally exposed to relatively large amounts of PCBs and dioxins, since these compounds are excreted in breast milk. For example, PCB levels were still approximately four times higher in 42‐month‐old children that were breast‐fed during infancy than in their formula‐fed counterparts that were predominantly prenatally exposed to PCBs and dioxins (Patandin et al., 1997). Since these neurotoxic compounds are able to interact with many processes of the CNS, including neurotransmitters and hormones that mediate brain development, the developing CNS is considered to be especially vulnerable to exposure to these neurotoxic compounds. Hence, prenatally, the CNS may be most vulnerable to harmful eVects of exposure to these compounds. Prenatal exposure can be regarded as chronic exposure of the developing brain. Postnatally, the CNS continues to develop rapidly, doubling in weight in the first year of life, reaching 90% of its adult size by 5 years of age. Much of this increase is due to an increase in neuronal maturation, production of glial cells, outgrowth of dendrites and axons, formation of synapses, and myelination of axons (Dodgson, 1962). Moreover, extensive cell death and synapse elimination takes place postnatally. These postnatal maturation processes

52

Hestien J. I. Vreugdenhil and Nynke Weisglas-Kuperus

may be especially vulnerable to adverse eVects of lactational exposure to PCBs and dioxins. The maturation rates vary for diVerent brain structures. Therefore, lactational exposure to PCBs and dioxins can be hypothesized to cause structure‐related functional diVerences, depending on the time window of exposure. For example, during the first 2 years of life in humans, functional cortical activity increases earliest in the sensorimotor and occipital cortices, before 3 to 6 months, the auditory and visual association cortices from 4 to 7 months, and latest in the frontal cortex, after 6 to 12 months (Chiron et al., 1992; Chugani et al., 1987). Moreover, timing of maximum brain growth, maximum synaptic density, dendritic arborizations, and myelination, all occur first in primary motor and sensory areas and later in the frontal cortex (Barkovich & Kjos, 1988; Barkovich et al., 1988; Becker et al., 1984; Huttenlocher & Dabholkar, 1997; Mrzljak et al., 1990).

A.

Perinatal Exposure to PCBs and Dioxins and Neurodevelopmental Outcomes

1. ACCIDENTAL EXPOSURE

Two accidents (‘‘Yusho,’’ Japan, 1968, and ‘‘Yu Cheng,’’ Taiwan, 1979) clearly showed the neurotoxic potential of prenatal exposure to these compounds. Large populations were accidentally exposed for relatively short periods to rice oil that was contaminated during the manufacturing process with heat transfer fluids containing PCBs, PCDFs, and polychlorinated quarterphenyls (PCQs). Children born to exposed Yusho mothers were described as dull and inactive at 6 years of age and had IQs averaging 70 (Harada, 1976). Cognitive functions were more thoroughly addressed in the Yu Cheng cohort (n ¼ 118), showing consistent cognitive delays of 5 points from 4 to 7 years of age compared to a matched control group (Chen et al., 1992; Lai et al., 1994). In children born up to 6 years after the incident, cognitive abilities were comparably aVected (Chen et al., 1992; Lai et al., 1994). Moreover, in 7‐ to 12‐year‐old Yu Cheng children, latencies and amplitudes of the P300 peak of an auditory event related potential, reflecting CNS mechanisms that evaluate and process relevant stimuli, were respectively longer and decreased in the exposed oVspring compared to their matched controls (Chen & Hsu, 1994). The measured P300 latencies in that study were inversely correlated with IQs. In the Yu Cheng cohort at 6, 7, 8, and 9 years of age, more spatially related cognitive abilities were diVerently aVected in boys and girls. Only the exposed boys scored lower than their nonexposed matched controls (Guo et al., 1995). These results, therefore, may have provided the

PCBS AND DIOXINS

53

first evidence of sex steroid hormone–modulating eVects of PCBs and dioxins on cognitive development in humans. 2. ENVIRONMENTAL EXPOSURE

The neurodevelopmental eVects described in the Yusho and Yu Cheng cohorts leave little doubt that high levels of prenatal exposure to mixtures of PCBs and dioxins result in neurotoxic eVects of these compounds in humans. Subtle neurodevelopmental eVects of perinatal exposure to PCBs and dioxins have also been described in several cohorts of children that were perinatally exposed to environmental levels of PCBs and dioxins (Darvill et al., 2000; Jacobson & Jacobson, 1996; Koopman‐Esseboom et al., 1996; Patandin et al., 1999b; Rogan & Gladen, 1991; Walkowiak et al., 2001). In these cohort studies, neurological, cognitive, and psychomotor aspects have been studied prospectively. The largest PCB cohorts include two cohorts that were selected based on maternal consumption of PCB‐contaminated fish from the North American Great Lakes: the Lake Michigan cohort (n ¼ 313) that was recruited between 1980 and 1981 (Jacobson et al., 1984a,b) and the more recently (1991–1994) recruited Oswego cohort (n ¼ 293) (Lonky et al., 1996). Another large cohort study has been executed in North Carolina, consisting of 912 mother–infant pairs that were recruited from a general population between 1978 and 1982 (Rogan et al., 1986a). In Europe, the main cohort studies include cohorts in Denmark, The Netherlands, and Germany. The two Danish cohorts were recruited in the Faeroe Islands: the first cohort consists of 435 children born between 1986 and 1987 (Grandjean et al., 1992), the second cohort was recruited from 1994 to 1995 (n ¼ 192), as part of a multicenter cohort study in which the Dutch PCB/dioxin study and a German study participated as well. The Danish cohorts are diVerent from other Northern European cohorts, due mainly to local dietary habits that include consumption of pilot whale blubber and whale meat. In these children, PCB levels were higher compared to levels in Northern Europe, whereas dioxin levels were comparable (Grandjean et al., 1995). The Dutch cohort (n ¼ 418) (Koopman‐Esseboom et al., 1994a) and German cohort (n ¼ 171) (Winneke et al., 1998), respectively, recruited between 1990–1992 and 1994–1995, both consist of mother–infant pairs that were drawn from the general population. The cohorts had similar inclusion criteria and used similar neurodevelopmental tests. In the Dutch cohort, however, restrictions were applied on the number of included breast‐fed children to study lactational exposure to PCBs and dioxins more thoroughly. Half of the recruited population had been breast‐fed for at least 6 weeks during infancy and the other half was fed with formula milk in which PCBs and dioxins were not

54

Hestien J. I. Vreugdenhil and Nynke Weisglas-Kuperus

detectable. The formula‐fed children represent children that were exposed mainly prenatally to PCBs and dioxins. The study design, inclusion and exclusion criteria, and PCB and dioxin measurements applied in the Dutch PCB/dioxin study will be presented in more detail. 3. NEURODEVELOPMENTAL EFFECTS

Neonatal neurological eVects of prenatal exposure to PCBs include deficits such as poorer autonomic regulation and more abnormal reflexes (Jacobson et al., 1984b; Lonky et al., 1996), hypotonia (Huisman et al., 1995a; Rogan et al., 1986b), and hyporeflexia (Rogan et al., 1986b). At 18 months of age, prenatal exposure to PCBs was negatively associated with the neurological condition in the Dutch PCB/dioxin cohort (Huisman et al., 1995b); however, this adverse eVect was not seen on the neurological condition in these children at 42 months of age (Lanting et al., 1998b). Assessment of standardized developmental tests, measuring general cognitive and psychomotor abilities, showed negative eVects of prenatal exposure to PCBs on psychomotor abilities until 2 years of age in the North Carolina (Gladen et al., 1988; Rogan & Gladen, 1991) and in the Dutch cohort at 3 months of age (Koopman‐Esseboom et al., 1996). Cognitive eVects of prenatal exposure to PCBs were seen at 7 months of age (Winneke et al., 1998) and more pronounced negative eVects were seen on more matured general cognitive abilities measured at 42 months (Patandin et al., 1999b; Walkowiak et al., 2001) and at 11 years of age (Jacobson & Jacobson, 1996). In the North Carolina study, however, prenatal exposure to PCBs was not related to cognitive and psychomotor abilities at 3, 4, and 5 years of age (Gladen & Rogan, 1991). Adverse eVects of prenatal exposure to PCBs have also been described on more specific cognitive domains, such as processing time, attention, and memory skills (both verbal and numerical auditory memory) in children at 4 years of age (Jacobson et al., 1990, 1992). Moreover, negative relations between prenatal PCB exposure and verbal comprehension skills at 42 months of age (Patandin et al., 1999b) and 11 years of age (Jacobson & Jacobson, 1996) have been described, in addition to verbal IQs and concentration skills (Jacobson & Jacobson, 1996). EVects of lactational or postnatal exposure to PCBs and dioxins have been detected in a few studies. In the Dutch cohort, psychomotor abilities at 7 months of age were decreased in children that were breast‐fed with relatively high concentrations of PCBs and dioxins (Koopman‐Esseboom et al., 1996). At 42 months of age, in the German cohort, negative eVects of postnatal exposure have been described on general cognitive abilities (Walkowiak et al., 2001).

PCBS AND DIOXINS

55

The results of the neurodevelopmental studies from birth to 42 months of age in the Dutch PCB/dioxin cohort are summarized in Table I.

III.

BEHAVIORAL ANIMAL STUDIES

The potential of subtle neurodevelopmental eVects of perinatal exposure to environmental levels of PCBs and dioxins seen in human studies is supported by the results of behavioral animal studies. Perinatal exposure to PCBs and dioxins has been related to several motor deficits, including impaired development of the righting reflex in rats and in mice with impaired ability to remain on a rotating rod (Overmann et al., 1987; Thiel et al., 1994). Moreover, in mice, perinatal exposure to a dioxin-like PCB congener was related with ‘‘spinning’’ behavior, diminished grip strength, and ability to traverse a wire rod (Tilson et al., 1979). Perinatal exposure to a PCB mixture resulted in impairment on several tasks that involve acquisition or recollection of spatial information, including impaired performance on spatial (based on the location of an object) discrimination reversal tasks (Bowman et al., 1978; Schantz et al., 1989, 1991) and decreased accuracy on a spatial delayed alteration task in monkeys (Levin et al., 1988; Schantz et al., 1991). In both tasks, memory and attentional processes are involved. Since the accuracy deficit did not worsen with increasing delay, the eVect was interpreted not as a memory impairment but rather as failure of attentional processes (Schantz et al., 1991). Monkeys that were perinatally exposed to a mixture of PCBs also performed diVerently on a fixed interval scale (Mele et al., 1986). In this task, a range of functions is assessed including inhibitory processes, maximal response rates, and temporal organization of behavior (Rice, 1988). The exposed monkeys showed disruptions in the temporal pattern of responding and slight elevations in their response rate (Mele et al., 1986). It has been suggested that in some of these behavioral deficits, processes related to the prefrontal cortex are involved in the mechanism of neurotoxic action of PCBs, potentially including mesocortical dopaminergic projections that terminate in the prefrontal cortex (Schantz et al., 1989, 1991). The deficit patterns on the discrimination reversal learning task (Schantz et al., 1989, 1991) and on the delayed spatial alteration showed similarities with deficits of monkeys with lesions to the dorsolateral area of the prefrontal cortex (Goldman et al., 1971). However, the current knowledge on brain structure‐related eVects of perinatal exposure to PCBs is too limited to support the hypothesis of prefrontal cortex involvement in the mechanism of eVect.

TABLE I SIGNIFICANT ASSOCIATIONS BETWEEN PERINATAL EXPOSURE TO PCBS AND DIOXINS AND NEURODEVELOPMENTAL OUTCOMES FROM 2 WEEKS TO 42 MONTHS OF AGE IN THE DUTCH COHORT Age

Cohorta

Neurological condition

2 wks

RþG

SPCBbreast milk, Total TEQ

Psychomotor development PDI, Bayley Scales of Infant Abilities Psychomotor development PDI, Bayley Scales of Infant Abilities Neurological condition

3m

R

SPCBmaternal

7m

R

Dioxin TEQ

18 m

RþG

SPCBmaternal/cord

42 m

RþG

SPCBmaternal/cord

42 m

R

SPCBmaternal/cord

Outcome variable

Exposure variable

56 General cognitive abilities K‐ABCc: Cognitive, Sequential & Simultaneous processing scale Verbal comprehension Reynell Developmental Language Scales

EVect description Higher breast milk levels of PCBs and dioxins were related with lower NOSb and higher incidence of hypotonia (Huisman et al., 1995a). Higher prenatal exposure was related with lower PDI scores (Koopman‐Esseboom et al., 1996). The highest exposed BF children (33%) scored lower than the less exposed BF children and comparable to FF children (Koopman‐Esseboom et al., 1996) Higher prenatal exposure was related to lower NOSb (Huisman et al., 1995a). Higher prenatal exposure was related with lower scores on the three scales. EVects were more pronounced in the FF group, lacking significance in the BF group (Patandin et al., 1999b). Higher prenatal exposure was significantly related with lower scores in the FF group, and not in the BF group (Patandin et al., 1999b).

Attentional processes Free play observation

42 m

R

SPCBmaternal/cord

Reaction time and sustained attention Computerized vigilance task

42 m

R

SPCBcord/ SPCB42 months

Problem Behavior Teacher CBCLd

42 m

R

Behavior Groninger Behavioral Scale (GBO)

42 m

R

SPCBmaternal/cord, SPCBbreast milk, Total TEQ SPCB42 months

Higher prenatal exposure was related with less episodes of high-level play, suggestive of less attentional abilities (Patandin et al., 1999c). Prenatal PCB exposure was related with more errors in the beginning of the task, suggestive of less focused attention (Patandin et al., 1999c). SPCB levels at 42 months were related with longer reaction times and a higher slope, suggestive of less sustained attention (Patandin et al., 1999c). Prenatal PCB and dioxin exposure was related to a higher prevalence of Withdrawn/Depressed behavior (Patandin et al., 1999c). SPCB levels at 42 months were related with a higher score on the GBO questionnaire, indicating more hyperactive behavior (Patandin et al., 1999c).

57

SPCB ¼ Sum of PCBs, IUPAC nos. 118, 138, 153, and 180 in maternal plasma measured during pregnancy, in cord plasma, or in breast milk. SPCB42 months ¼ Sum of PCBs, IUPAC nos. 118, 138, 153, and 180, measured in plasma of 42-month old children, representing mainly lactational transfer of maternal PCBs (the breast‐fed group) and in part during gestation (the formula‐fed group) [Patandin, 1997 #59]. TEQ ¼ Toxic Equivalent; Total TEQ ¼ sum of TEQs of 8 dioxin like PCBs (IUPAC nos. 77, 105, 118, 126, 156, and 169) and 17 dioxin congeners measured in breast milk. Shaded cells are results that give evidence of negative eVects of lactational exposure. a R ¼ Rotterdam and G ¼ Groningen cohort. b NOS ¼ Neurological optimality score. c K‐ABC ¼ Dutch Kaufman Assessment Battery for Children. d CBCL ¼ Child Behavior Checklist.

58

Hestien J. I. Vreugdenhil and Nynke Weisglas-Kuperus IV.

A.

HUMAN NEURODEVELOPMENTAL PCB AND DIOXIN RISK ASSESSMENT

Prenatal Versus Postnatal Exposure to PCBs and Dioxins

Although much larger quantities of PCBs and dioxins are transferred to the child postnatally through lactation than prenatally, human epidemiological studies suggest more pronounced neurodevelopmental eVects of prenatal exposure to PCBs and dioxins compared to postnatal exposure to these compounds. However, several animal studies have shown profound behavioral impairments induced by postnatal exposure to low levels of a mixture of ortho‐substituted PCB mixtures that is representative of the PCB mixture found in human milk. In these monkeys, impaired performance was seen on spatial learning tasks, including impairment in learning a delayed spatial alteration task (Rice, 1998a, 1999) and more perseverative responding (Rice, 1999; Rice & Hayward, 1997). Moreover, slower acquisition of a fixed interval task and inability to inhibit inappropriate responding have been associated with postnatal exposure to PCB mixtures (Rice, 1997, 1999). These impairments suggest a discrimination learning deficit and diYculty in adaptively changing response patterns—deficits that are suggestive of involvement of prefrontal cortex processes in the neurotoxic mechanism of PCBs and dioxins (Rice, 1999). EVects of lactational exposure on these functions need to be addressed more thoroughly in the human studies. In human studies, addressing neurodevelopmental eVects of lactational exposure to PCBs and dioxins is complex. Breast milk contains several substances, such as several long‐chain polyunsaturated fatty acids, that are not available in formula milk. These acids are important constituents of the structural lipids of nonmyelinated cell membranes in the developing nervous system and are essential for growth, function, and integrity (Innis, 1994), and may therefore be important for optimal brain development. A meta‐ analysis of studies that addressed neurodevelopmental benefits of breast‐ feeding provided evidence for enhanced early cognitive development that sustained through childhood and adolescence (Anderson et al., 1999), taking into account a number of studies which suggested that diVerences in cognitive development were attributable to the generally associated diVerences in social economic conditions. The latter aspect forms another complicating feature of assessing neurodevelopmental eVects of lactational exposure: in Western societies, parents who choose to breast‐feed their child are likely to be diVerent in several parental and home environmental conditions. These aspects may influence the susceptibility to harmful eVects of perinatal exposure to PCBs and dioxins. The results of prenatal exposure to PCBs and dioxins on general cognitive abilities at 42 months of age in the Dutch cohort

PCBS AND DIOXINS

59

may illustrate the complexity of exploring eVects of exposure to PCBs and dioxins in breast‐fed children. At 42 months of age, adverse eVects of prenatal exposure to these compounds were more pronounced in the formula‐fed group compared to the breast‐fed group of children (Patandin et al., 1999b). B.

Sex Steroid–Related Behavioral PCB and Dioxins Effects

Neurotoxic eVects of perinatal exposure to PCBs and dioxins that cause developmental deficits may be mediated by endocrine‐disrupting properties of PCBs and dioxins. For example, steroid hormones play a mediating role in CNS development and influence not only reproductive but also nonreproductive behaviors that show sex diVerences (Fitch & Denenberg, 1998; Matsumoto, 1991). In animals, some eVects of perinatal exposure to PCBs and dioxins on nonreproductive behaviors have been reported. For example, a feminizing eVect on sweet preference was found in male rats that were perinatally exposed to a PCB mixture representative to PCBs found in human milk. In their female counterparts, sweet preference was not aVected (Hany et al., 1999). In contrast, prenatal exposure to a dioxin (TCDD) and coplanar (dioxin-like) PCBs decreased sweet preference in female rats, which can be interpreted as a masculinizing eVect in females. In the exposed males, no change in sweet preference was seen (Amin et al., 2000). The animal studies suggest both feminizing and masculinizing eVects of perinatal exposure to PCBs and dioxins on sex‐specific behavior, which may suggest steroid hormone–mediated eVects of PCB and dioxin exposure. In human studies, eVects of perinatal exposure to PCBs and dioxins on nonreproductive sex‐specific behavior have hardly been addressed. The only study that provided some evidence for steroid hormone–mediated behavioral eVects of prenatal exposure to PCBs and dioxins is the study in the highly exposed children of the Yu Cheng cohort. In this cohort, more spatially related cognitive abilities, which generally show some sex diVerences, were diVerently aVected in boys and girls. Only the exposed boys scored lower than their nonexposed matched controls (Guo et al., 1995). C.

Neurodevelopmental Interstudy Differences

The results of epidemiological studies that address neurodevelopmental eVects of perinatal exposure to environmental levels of PCBs show inconsistencies both between cohorts and within cohorts at diVerent ages. These diVerences in outcome do not necessarily undermine conclusions that prenatal exposure to environmental levels of PCBs is related to subtle harmful eVects on child neurodevelopment. The diVerences could be related to a

60

Hestien J. I. Vreugdenhil and Nynke Weisglas-Kuperus

number of factors, including diVerences in exposure assessment techniques, diVerences in composure of environmental PCB mixtures, and diVerences in exposure levels. Moreover, diVerences in parental and home environmental conditions or the occurrence of other neurotoxic agents, which may confound relationships between exposure and neurodevelopmental outcome, may have led to diVerences in results. Additionally, diVerent neurodevelopmental outcome variables have been used in the cohort studies. Furthermore, addressing neurodevelopmental eVects of perinatal exposure to PCBs and dioxins as well as comparison of eVects assessed by diVerent cohorts at diVerent ages is complicated by the fact that the outcome variables are developmental qualities. EVects of perinatal exposure to PCBs and dioxins may not become evident until further maturation of the child. Some of these issues will be discussed in the following text. 1. EXPOSURE LEVELS

Exposure levels in the cohorts are diYcult to compare since, in the earlier American studies, diVerent assessment techniques have been used compared to the later initiated studies. In an eVort to compare exposure levels of several cohorts, median levels of PCB153 in maternal blood were used for comparison (Longnecker et al., 2003). This congener is always among the PCB congeners present at the highest concentration and constitutes a large proportion of the PCBs mixtures in all studies. That study showed that the median Dutch PCB153 level (0.10 mg/g lipid) was comparable to the median level in the Lake Michigan cohort (0.12 mg/g lipid), the North Carolina cohort (0.08 mg/g lipid), and the German median levels (0.14 mg/g lipid). The median exposure level in the Faeroe Islands cohort (recruited between 1994 and 1995) was 3 to 4 times higher than in these studies (0.45 mg/g lipid). 2. CONFOUNDING VARIABLES AND POTENTIAL DIFFERENCES IN SUSCEPTIBILITY TO EFFECTS OF PCB AND DIOXIN EXPOSURE

In the epidemiological studies, subjects could not be randomly assigned to predetermined levels of exposure or type of feeding during infancy. Samples were based on volunteer mother–infant pairs and parents were free in choosing the type of infant feeding they preferred because of acceptable ethical concerns. Therefore, all cohort studies have made eVorts to assess potential confounding variables, to adjust for these variables when studying the relation between perinatal exposure to PCBs and dioxins and neurodevelopment. In Western societies, the relation between perinatal exposure to PCBs and dioxins and neurodevelopment is often confounded by parental and home environmental conditions. Due to the physical stability and accumulation of PCBs and dioxins in human tissues, PCB and dioxin body burdens are

PCBS AND DIOXINS

61

strongly related to maternal age at birth. Mothers at older age who give birth to a child are often higher educated and have higher IQs than women at younger age who give birth to a child. Maternal age may also reflect other aspects of social economic conditions as well as psychosocial age‐related attributes (Stein, 1985). Child development is a process in which structural changes and environmental experiences influence each other mutually. For example, many cognitive skills, including IQs, verbal and spatial abilities, and perceptual speed (Alarcon et al., 1998; Plomin & Loehlin, 1989; Posthuma et al., 2001), have been shown to be under genetic influences. Environmental or psychosocial aspects, such as intellectual stimulation, organization of the home environment, verbal responsivity of the parents, variability of daily experience, and parental involvement also influence cognitive development (Bradley et al., 2001). In animal studies, environmental aspects influenced cortical diVerentiation and dendritic formation, thereby changing the functional connectivity of the nervous system. Several lines of evidence point toward the relationship between dendritic and synaptic changes and experiences and, more specifically, learning (Devoogd et al., 1985; Moser et al., 1994; Rosenzweig & Bennett, 1996; WolV et al., 1995). Moreover, numerous animal studies showed that environmental enrichment can compensate for and possibly even reverse some of the adverse eVects of developmental insults (Brenner et al., 1985; Diamond et al., 1975; Kolb, 1989). These studies suggest potential for structural and functional recovery throughout the cortical maturation period in animals. In humans, evidence of neural plasticity throughout the maturation period may be supported by results of studies in low birth weight children. These studies reported that in children at high biological risk, favorable early parental and home characteristics could compensate for or mask developmental delays (Landry et al., 1997; PfeiVer & Aylward, 1990; Weisglas‐ Kuperus et al., 1993). Hence, these genetic and environmental conditions are important predictors of cognitive development and can additionally be important in determining the vulnerability of an individual child or a given population to the eVects of neurotoxicants. Favorable parental and home environmental conditions may protect some groups against negative neurodevelopmental eVects of perinatal PCB and dioxin exposure. Evidence for this hypothesis is seen in the Dutch study showing less pronounced eVects of prenatal exposure to PCBs in breast‐fed children compared to formula‐fed children at 42 months of age (Patandin et al., 1999b). A reanalysis in the Lake Michigan cohort similarly showed that prenatal exposure to PCBs was related with lower IQs at 11 years of age in predominantly the group of formula‐fed children (n ¼ 56, 31%) (Jacobson & Jacobson, 2001). In the North Carolina cohort, prenatal exposure to PCBs

62

Hestien J. I. Vreugdenhil and Nynke Weisglas-Kuperus

was not related to later cognitive and motor development from 3 to 5 years of age, in contrast to the Lake Michigan and Dutch study. In the North Carolina cohort, a relatively high proportion of the population was breast‐ fed during infancy (88%). Moreover, the average years of college education in the North Carolina cohort was 3 years and in the Lake Michigan cohort 1 year. In the Dutch cohort, 40% of the mothers have finished high school and 30% of them finished professional and university training. Some of the diVerences in neurodevelopmental eVects of PCB exposure between study centers can therefore be hypothesized to be related to cohort diVerences in the levels of these conditions that are important to child development. 3. CONFOUNDING BY OTHER NEUROTOXIC COMPOUNDS

Due to the correlational feature of the epidemiological studies addressing eVects of perinatal exposure to PCBs and dioxins, relations between these compounds and outcome are potentially related to exposure to other neurotoxic compounds, such as methyl mercury and lead. For example, in the Faeroe study, in which the local diet consists predominantly of fish and fish products, PCB and dioxin levels were seen to be relatively high compared to other European studies, as were the levels of methyl mercury. Significant relations between prenatal exposure to PCBs and reaction time and (semantic) memory skills appeared to be mainly attributable to prenatal exposure to methyl mercury compounds (Grandjean et al., 2001). However, in children exposed to high levels of methyl mercury, eVects of prenatal exposure to PCBs on these outcome variables were more pronounced than in children exposed to lower levels of methyl mercury, suggesting a potential interaction between these neurotoxic compounds in their neurodevelopmental eVects. In the Lake Michigan cohort, mothers were selected based on their diet history on Lake Michigan PCB‐contaminated fish. Fish and other aquatic species often form the source of exposure to PCBs as well as other neurotoxic compounds, such as methyl mercury. The relations between neurodevelopment and prenatal PCB exposure as described in the Lake Michigan studies, therefore, may have been confounded by exposure to this compound. However, based on the congruence between the results of animal studies and several human cohort studies, it has been suggested that the deficits observed in the Lake Michigan studies result, at least in part, from PCB exposure (Rice, 1995). In contrast to the Lake Michigan study, the North Carolina, Dutch, and German cohorts were recruited from the general public which may reduce the risk of confounding by methyl mercury. In the Netherlands, PCB and dioxin exposure occurs mainly through dietary intake of predominantly dairy products, as well as processed food and meat and fish products (Patandin et al., 1999a). In the Dutch PCB/dioxin cohort, lead and

PCBS AND DIOXINS

63

cadmium levels in blood samples drawn from 18-month old children (n ¼ 151) were relatively low (Weisglas‐Kuperus et al., 2000) and not related to cognitive outcome at 42 months of age (Patandin et al., 1999b). 4. NEURODEVELOPMENTAL TESTS AND THE DEVELOPMENT OF COGNITIVE ABILITIES

The cohort studies also show diVerences in the neurodevelopmental testing protocols that were used to explore neurotoxic eVects of perinatal exposure to PCBs and dioxins. Neurodevelopmental assessment has occurred at diVerent ages using diVerent test materials, which complicates comparison of the diVerent cohorts, especially due to the developmental nature of cognitive and motor abilities and since some aVected functions may not become apparent until a more mature age. Most prospective longitudinal studies have assessed general cognitive and motor abilities by means of developmental tests that were reassessed repeatedly through childhood. Performance on the developmental tests reflects, especially at a more mature age, a broad range of domains of function, including memory, visuospatial abilities, verbal and quantitative reasoning, and attentional aspects. Although general cognitive development seems to be the most relevant outcome variable in risk assessment studies, because of its predictive feature for later outcome, general cognitive ability indices may be too general to assess subtle eVects of exposure to neurotoxic compounds. The general cognitive score can obscure important individual diVerences in specific cognitive profiles, since children with diVerent cognitive profiles can have comparable scores on this outcome variable. Moreover, it can be reasoned that general cognitive scores reflect the product of learning, which is strongly related to social economic aspects, rather than processes of learning. The development of general cognitive abilities may progress at diVerent rates. Reported negative eVects of prenatal exposure to PCBs at diVerent assessment times within one cohort do not resolve the question of whether the same children are aVected in their abilities at the diVerent assessment periods. Consequently, risk assessment studies into eVects of perinatal exposure to PCBs and dioxins on cognitive and motor abilities in children may benefit from addressing the level and course of the development of these abilities. Early PCB and dioxin exposure may induce changes in brain structures that continue to influence neurodevelopment during maturation, resulting in delayed eVects of functions that develop later in childhood. Especially when eVects of lactational exposure to PCBs and dioxins are addressed, structure‐ related functional diVerences potentially, depending on the time window of exposure, can be hypothesized due to diVerences in maturation rates of diVerent brain structures. The exploration of neurotoxic eVects of perinatal exposure to neurotoxic agents therefore should address more specific

64

Hestien J. I. Vreugdenhil and Nynke Weisglas-Kuperus

domains of cognitive functioning that can be assessed at a more mature age. These domains are not suYciently measured by developmental or IQ tests, since most domains are indicated by too few items to provide reliable measurement of domain‐specific performance.

V.

THE DUTCH PCB AND DIOXIN STUDY AT SCHOOL AGE

Children enrolled in the Dutch PCB/dioxin cohort (Rotterdam and Groningen cohort) were invited to participate in follow‐up assessment at 6 to 7 years of age and half of the Rotterdam cohort was invited at 9 years of age as well. General cognitive and motor abilities, gender role‐play behavior, and neuropsychological functions were assessed. A neurophysiological assessment was also included. A.

Aims of the Study at School Age

The general aim of this study was to describe neurodevelopmental eVects of perinatal exposure to environmental levels of PCBs and dioxins in normal Dutch children at school age, as well as on the development of general cognitive and motor abilities from 3 to 84 months of age. In addition, the goal was to gain more insight into potential compensating eVects of parental and home environmental conditions and breast‐feeding, as well as into neurotoxic mechanisms of eVects of perinatal exposure to these compounds. B.

Subjects and Inclusion and Exclusion Criteria

A total of 418 healthy mother–infant pairs were recruited from June 1990 to June 1991. Half of the study population was recruited in Rotterdam (n ¼ 207), a highly industrialized and densely populated area, and the other half in Groningen (n ¼ 211), a semi‐urban area in The Netherlands. Healthy pregnant women were asked by their obstetrician or midwife to participate in a prospective neurodevelopmental study. The cohort consists of Caucasian mother–infant pairs. Pregnancy and delivery had been without complications; instrumental deliveries or caesarian sections were excluded. Only first or second at term‐born infants (37–42 weeks of gestation) who had no congenital anomalies or diseases were included. Because of these criteria, the cohort of children can be presumed to be at relatively low risk for neurodevelopmental deficits. To study the eVects of prenatal as well as postnatal PCB and dioxin exposure, it was aimed to include an equal number of women who intended to breast‐feed their child for at least 6 weeks (BF) and women who intended to

PCBS AND DIOXINS

65

use formula‐feeding (FF). All infants in the FF group received formula from a single batch (Almiron M2, Nutricia NV, Zoetermeer, The Netherlands) from birth until 7 months of age. In this formula, concentrations of both PCBs and dioxins were below the detection limit. The medical ethics committee of the University Hospital Rotterdam/ Sophia Children’s Hospital, and the Academical Hospital Groningen approved the study design and the parents gave informed consent. C.

Exposure Measurements

The exposure variables that were used in these studies included PCB levels in maternal and cord plasma. Maternal plasma samples were collected from the mothers during the last month of pregnancy and cord plasma samples were collected directly after birth. These samples were analyzed by means of gas chromatography with electron capture detection (GC‐ECD) for four PCB congeners, International Union for Pure and Applied Chemistry (IUPAC) numbers 118, 138, 153, and 180 (Burse et al., 1989; Koopman‐ Esseboom et al., 1994a). Two weeks after delivery a 24‐hour representative breast milk sample was collected from the mothers who were breast‐feeding their children. These samples were analyzed for 17 most abundant dioxins (PCDDs and PCDFs) and three dioxin-like PCBs (IUPAC nos. 77, 126, 169) by means of gas chromatography–high‐resolution mass spectometry (GC‐HRMS). In these samples, 23 non-dioxin-like PCBs (IUPAC nos. 28, 52, 66, 70, 99, 101, 105, 118, 128, 137, 138, 141, 151, 153, 156, 170, 177, 180, 183, 187, 194, 195, and 202) were measured by GC‐ECD (Koopman‐Esseboom et al., 1994a). Toxic potency of the mixture of dioxins and dioxin-like PCBs was expressed by using the toxic equivalent factor approach (Van den Berg et al., 1998b). Prenatal exposure to PCBs is defined as the sum of the concentrations of the four PCB congeners measured in maternal plasma and in cord plasma. PCB and dioxin concentrations in breast milk were assessed shortly after birth and form an indirect measure of prenatal exposure (Rogan et al., 1986a). Postnatal exposure to PCBs and dioxins through lactation was estimated in the BF group by multiplying breast milk levels of PCBs, dioxin-like PCB TEQs (dioxin toxic equivalents), and dioxin TEQs with the numbers of weeks of breast‐feeding. D.

Cognitive and Motor Abilities at School Age

At school age, the Dutch version of the McCarthy Scales of Children’s Abilities (Van der Meulen & Smirkovsky, 1985) was used to assess the general cognitive abilities (General Cognitive Index) and memory and motor

66

Hestien J. I. Vreugdenhil and Nynke Weisglas-Kuperus

skills in children of the Rotterdam and Groningen cohort (n ¼ 418). From the original cohort, 90% (n ¼ 376) were willing to participate in this follow‐ up (mean age 6.7 years þ 0.3). The data of four children were excluded from the data analysis because of potential confounding pathology. Prenatal PCB and dioxin levels were comparable for the nonparticipating and participating children. Multiple linear regression analysis showed that, adjusted for confounding variables, prenatal exposure to PCBs and dioxins was not significantly related to cognitive and motor development at school age. Moreover, eVects of prenatal exposure on cognitive and motor abilities were not statistically diVerent for the two feeding groups. However, it appeared that eVects of prenatal exposure to PCBs and dioxins on cognitive and motor abilities were modified by parental and home environmental conditions (maternal age, parental education level and verbal IQ, and HOME score). The parental and home environmental conditions were strongly related to each other. Older maternal age was related to a higher parental education level and verbal IQ and higher scores on the HOME questionnaire, conditions that are considered to be relatively more favorable to child development. The impact of adverse eVects of prenatal exposure to PCBs and dioxins on cognitive and motor abilities was suggested to increase as parental and home environmental conditions were lower. In children raised in relatively more favorable parental and home environmental conditions, subtle eVects of prenatal exposure to PCBs and dioxins were not detectable. EVect modifications of PCB and dioxin exposure by maternal age, parental education level and verbal IQ, and HOME scores could not be explored simultaneously in one regression analysis due to the problem of multicollinearity. The results did not show evidence of negative eVects of lactational exposure to PCBs and dioxins on cognitive and motor outcome, nor of eVect modification of lactational exposure by parental and home environmental characteristics. We concluded that neurotoxic eVects of prenatal exposure to environmental levels of PCBs and dioxins may persist into school age and may result in subtle cognitive and motor delays. The results of this study suggest that parental and home environmental conditions influence the consequences of the neurotoxic eVects on cognitive and motor development (Vreugdenhil et al., 2002a). E.

The Development of General Cognitive and Motor Abilities from 3 to 84 Months of Age

A disadvantage of studying relations between perinatal exposure to PCBs and dioxins and cognitive and motor abilities at a certain age is that the developmental course of these abilities is not captured. Therefore, eVects of perinatal exposure to PCBs, measured in maternal plasma, on

PCBS AND DIOXINS

67

the development of cognitive and motor abilities, as assessed in the Rotterdam cohort at 3, 7, 18, 42, and 84 months of age, were described using the method of random regression modeling (RRM). Moreover, important predictors of general cognitive and motor development from 3 to 84 months of age were identified in this study. Data on cognitive and motor abilities were available for all analyzable children (excluding children with potential confounding pathology, n ¼ 3). In the initial RRM models, all selected variables of potential relevance to cognitive and motor development were included. In these models, higher levels of prenatal PCB exposure were significantly related to a lower level of cognitive and motor development from 3 to 84 months of age. In this study, the problem of multicollinearity when including the four previously described interaction variables of prenatal PCB exposure and parental and home environmental variables simultaneously in the regression model was solved by centering these variables as well as their main terms. Simultaneous inclusion of these variables showed that eVects of prenatal exposure to PCBs on the level of cognitive development were significantly modified by maternal age, overruling eVect modification by the other parental and home environmental conditions. In children born to younger mothers, eVects of prenatal exposure to PCBs on cognitive development were suggested to be more pronounced than in children born to older mothers, a condition that is likely to reflect more favorable parental and home environmental conditions for child development. Prenatal PCB levels, and modification by maternal age, along with parental education level and verbal IQ and HOME scores, were important determinants of the level of cognitive development. Motor development was eYciently estimated by prenatal PCB levels, including its modification by HOME scores along with parental education levels. EVects of prenatal PCB exposure on motor development were more pronounced when the HOME scores were lower. The results provided no evidence of negative eVects of lactational exposure to PCBs on cognitive or motor development and neither were maternal (prenatal) thyroid hormone levels related to these outcomes. These results provided evidence of adverse eVects of prenatal exposure to PCBs on the level of cognitive and motor development, eVects that may be modified by conditions that are favorable to child development. Compared to the large positive eVects of more optimal parental and home environmental conditions, the negative eVects of prenatal PCB exposure on cognitive development from 3 to 84 months of age were relatively small. EVects of prenatal exposure were more pronounced for motor than for cognitive development. Motor development may therefore be a more sensitive outcome to detect prenatal exposure to PCBs and related compounds than is cognitive development (Vreugdenhil et al., 2002c).

68 F.

Hestien J. I. Vreugdenhil and Nynke Weisglas-Kuperus Sex‐Specific Play Behavior

As part of the first follow‐up study at school age, play behavior was assessed by means of the Pre‐School Activity Inventory (PSAI) in the Rotterdam cohort (Golombok & Rust, 1993). The PSAI assesses masculine and feminine play behavior scored on three subscales: Masculine, Feminine, and Composite. One hundred sixty PSAI questionnaires were returned (mean age þ SD: 7.5 years þ 0.4). Higher prenatal PCB levels were related with less masculinized play behavior in boys and with more masculinized play behavior in girls. Higher prenatal dioxin levels, available for BF children, were associated with more feminized play in boys as well as in girls, assessed by the Feminine scale. There was no evidence that lactational exposure to PCBs and dioxins was related to play behavior in the total BF group nor in boys and girls separately. The results are suggestive of steroid hormone involvement in the neurotoxic mechanism of action of prenatal exposure to environmental levels of PCBs and dioxins (Vreugdenhil et al., 2002b).

G.

Neuropsychological Functions

Half of the Rotterdam cohort, the lowest prenatally exposed (p25; n ¼ 26) and the highest prenatally exposed children (p75; n ¼ 26) of both feeding groups (total n ¼ 104) were invited to participate in neuropsychological and neurophysiological assessments at 9 years of age. From the invited children, 80% (n ¼ 83) were willing to participate in this follow‐up study (mean age þ SD: 9.2 þ 0.2). Exposure levels of the participating and nonparticipating children were comparable. The assessment of neuropsychological functions included the Rey Complex Figure task, the Auditory–Verbal Test, the Simple Reaction Time task, and the Tower of London (TOL). Prenatally high‐exposed children had, adjusted for confounding variables, longer reaction times and more variation in their reaction times, and lower scores on the TOL than did prenatally low‐exposed children. On the latter task, assessing predominantly executive or planning functions, in contrast to the other tasks, children that were BF for a long period (>16 weeks) scored significantly lower than did FF children. The results of this study are suggestive of multifocal or diVuse neurotoxic eVects of prenatal exposure to PCBs and related compounds. For lactational exposure, the negative eVect on the TOL scores may suggest that processes related to the prefrontal cortex are involved in the neurotoxic mechanism of exposure to PCBs and related compounds. This can be hypothesized since the frontal cortex shows a delayed maturation rate compared to other brain regions and developing brain structures are more

PCBS AND DIOXINS

69

vulnerable to exposure to PCBs and dioxins. A complex task such as the TOL may also serve as a sensitive outcome parameter to assess neurotoxic eVects of early exposure to PCBs and related compounds (Vreugdenhil et al., 2004a). H.

Neurophysiological Endpoints

The P‐300 is considered to be a cognitive component of event‐related brain potentials and occurs with a latency of about 300 milliseconds when a person is actively processing (‘‘attending to’’) incoming stimuli. Prenatally high‐exposed children had significantly longer P‐300 latencies than prenatally low‐exposed children, adjusted for confounding variables. The results gave no evidence of diVerences in P‐300 latencies related to lactational exposure to PCBs and dioxins. Instead, a longer duration of breast‐feeding (>16 weeks) was associated with shorter P‐300 latencies compared to children that were BF for 6 to 16 weeks and to FF children. No diVerences in P‐300 amplitudes were seen relative to prenatal or postnatal exposure to PCBs and dioxins or to the duration of breast‐feeding. These results suggest that prenatal exposure to PCBs and dioxins delays CNS mechanisms that evaluate and process relevant stimuli at school age, whereas breast‐feeding accelerates these mechanisms (Vreugdenhil et al., 2004b).

VI. A.

DISCUSSION

Neurotoxic Mechanisms

Prenatal exposure to PCBs and dioxins can be regarded as chronic exposure of the developing CNS and many processes of the CNS are likely to be sensitive to exposure to PCBs and dioxins, including neuronal and glial cells, neurotransmitters, and endocrine systems (Brouwer et al., 1995, 1999; Mariussen & Fonnum, 2001; Tilson & Kodavanti, 1998). Consequently, eVects of prenatal exposure to PCBs and dioxins are likely to be of multifocal or diVuse nature. The results of the Dutch PCB/dioxin study and other prospective human PCB studies suggest eVects of prenatal exposure to PCBs on several neurodevelopmental outcome variables, including general cognitive and motor development (Gladen et al., 1988; Jacobson & Jacobson, 1996; Koopman‐Esseboom et al., 1996; Patandin et al., 1999b; Rogan & Gladen, 1991; Vreugdenhil et al., 2002a; Walkowiak et al., 2001; Winneke et al., 1998), verbal comprehension skills (Jacobson & Jacobson, 1996; Patandin et al., 1999b), processing speed (Grandjean et al., 2001; Vreugdenhil et al., 2004a), attention and concentration (Jacobson & Jacobson, 1996;

70

Hestien J. I. Vreugdenhil and Nynke Weisglas-Kuperus

Patandin et al., 1999c; Vreugdenhil et al., 2004a), memory skills (Jacobson & Jacobson, 1996; Vreugdenhil et al., 2002a), planning or executive functions (Vreugdenhil et al., 2004a), and on a neurophysiological endpoint that assesses processing and evaluation of auditory stimuli (Vreugdenhil et al., 2004b). In the neuropsychological study, scores on some tests were not related to perinatal exposure to PCBs and dioxins. This may reflect diVerences in sensitivity of neuropsychological tests to measure subtle neurotoxic eVects of perinatal exposure to neurotoxic compounds. The diVerence in sensitivity in a relatively small cohort may aVect the power to detect eVects and may, therefore, result in missing eVects of perinatal exposure to PCBs and dioxins (increasing Type II errors). Postnatally, maturation of diVerent areas in the brain occurs at diVerent rates. The frontal cortex shows the slowest maturation rate. Since developing CNS structures are known to be especially vulnerable to adverse eVects of exposure to PCBs and dioxins, structure‐related eVects of lactational exposure can be hypothesized. Some evidence in support of this hypothesis can be found in the finding that performance on the TOL was the only outcome that was suggested to be related to lactational exposure to PCBs. In planning or executive functions, processes of the prefrontal cortex are especially involved, in which higher cortical functions from several areas of the brains are integrated. In monkeys that were only exposed to PCBs through lactation, PCB‐induced behavioral deficits were also suggestive of prefrontal cortex involvement (Rice, 1999). Moreover, brain dopaminergic systems have been shown to be aVected (Mariussen et al., 2001; Seegal et al., 1997) by exposure to PCBs and some major dopaminergic pathways are known to serve the prefrontal cortex (Saper et al., 2000). Another important aspect of neurotoxic eVects of prenatal exposure to PCBs and dioxins is that the neurodevelopmental consequences of neurotoxic actions of prenatal exposure to environmental levels of PCBs and dioxins may be influenced by parental and home environmental conditions. Global measurements of cognitive and motor abilities are relatively strongly related to parental and home environmental conditions. The results of the Dutch PCB/dioxin study are suggestive of compensation of negative eVects of perinatal exposure on cognitive and motor development in children raised in more favorable parental and home environmental conditions or of cumulative deficits in children raised in less favorable conditions. These results may be in line with animal studies which show a positive impact of an enriched environment on the eVects of brain lesions (Brenner et al., 1985; Diamond et al., 1975; Kolb, 1989) and with some human studies addressing eVects of perinatal exposure to lead and methyl mercury (Bellinger et al., 1988; Winneke & Kraemer, 1984) and the outcome in very low birth

PCBS AND DIOXINS

71

weight children (Landry et al., 1997; PfeiVer & Aylward, 1990; Weisglas‐ Kuperus et al., 1993). Neurotoxic eVects of perinatal exposure to PCBs and dioxins may be mediated by hormone‐disrupting properties of PCBs and dioxins, for example, in regard to steroid and thyroid hormone systems. The (sex‐specific) eVects of perinatal exposure to PCBs and dioxins on childhood play behavior suggest mediation of behavioral eVects of prenatal PCB and dioxin exposure by the sex‐steroid hormone system. However, evaluation of the relation between prenatal steroid hormone status and PCB and dioxin exposure is needed to further confirm these findings. In this cohort, maternal and infant thyroid hormone levels were related to maternal levels of PCBs and dioxins. Prenatal alterations in prenatal thyroid hormone levels may cause long‐lasting neurodevelopmental deficits (Porterfield, 1994; Rovet & Ehrlich, 1995). However, in the Dutch PCB dioxin study, maternal thyroid hormone status was not statistically related to the level of cognitive and motor development from 3 to 84 months of age. The presently used analyses, therefore, do not provide evidence that prenatal thyroid hormone status is one of the key mechanisms in the neurotoxic eVects of prenatal exposure to PCBs and dioxins on general cognitive and motor development. Animal studies show diVerences in the neurotoxic eVects of nonplanar PCBs and dioxins and dioxin-like PCBs (Fischer et al., 1998; Tilson & Kodavanti, 1997). Humans are exposed to complex mixtures of PCBs and dioxins and their related compounds, such as hydroxylated PCBs. Not finding associations between outcome variables and TEQs or total TEQs may suggest that neurotoxic eVects of PCBs and dioxins were not mediated by the Ah receptor, as is in line with animal studies that report more pronounced neurotoxic actions of nonortho‐substituted PCB congeners than of dioxins and dioxin-like PCBs. The studies presented here show more pronounced eVects on general cognitive and motor abilities of the four nonplanar PCBs (IUPAC nos. 118, 138, 153, and 180) as assessed in plasma compared to the dioxin TEQs and total TEQs assessed in breast milk. However, based on these results, we believe that we cannot diVerentiate eVects of diVerent types of congeners, since the levels of diVerent types of congeners were strongly related (Koopman‐Esseboom et al., 1994a). Moreover, dioxins as well as a more elaborate number of PCB congeners were assessed in breast milk that was available for only half of the cohort. Analyses in this subpopulation may have increased the risk of Type II errors, which may consequently increase the risk of missing associations. However, in regard to play behavior, some evidence of diVerent neurotoxic eVects of PCBs and dioxins can be hypothesized. Prenatal exposure to the sum of the four nonplanar PCBs was suggested to be related with opposite eVects in boys and girls on masculine play behavior, whereas higher levels of prenatal

72

Hestien J. I. Vreugdenhil and Nynke Weisglas-Kuperus

exposure to dioxins, expressed in TEQs, were related to more feminized play behavior in both boys and girls in a similar direction. In conclusion, the mechanisms of neurotoxic eVects of prenatal exposure to PCBs and dioxins may include multifocal, or diVuse, neurodevelopmental impairments. Due to diVerences in the maturation of the CNS, lactational exposure may be related to more focal eVects, in which processes related to the prefrontal cortex are suggested to be involved. Neurotoxic eVects on neurodevelopmental outcome that is more strongly related to parental and home environmental conditions may be modified by these conditions. Moreover, steroid hormones are suggested to be involved in the neurotoxic mechanism of eVects of prenatal exposure to PCBs on a sex‐specific nonreproductive behavior. B.

Is Breast‐Feeding Safe?

Although BF children are exposed to relatively large amounts of PCBs and dioxins, negative eVects of lactational exposure to PCB and dioxins are only suggested on the scores on the TOL. The results of this study, therefore, may indicate that eVects of prenatal exposure to PCBs and dioxins are more pronounced than eVects of exposure to PCBs and dioxins through lactation. This is in agreement with most of the human studies that address perinatal exposure to environmental levels of PCBs and dioxins (Gladen et al., 1988; Jacobson & Jacobson, 1996; Jacobson et al., 1990; Rogan & Gladen, 1991). Only two studies have described adverse eVects of lactational exposure on scores on these developmental tests. Lactational exposure to PCBs and dioxins was related to lower psychomotor abilities at 7 months of age (Koopman‐ Esseboom et al., 1996) in the Dutch study and to lower general cognitive abilities at 42 months of age in the German cohort (Walkowiak et al., 2001). There are some methodological aspects that should be considered in risk assessment studies that address neurodevelopmental eVects of lactational exposure to PCBs and dioxins, especially in Western societies. Based on the studies described in the previous paragraph, it can be hypothesized that negative eVects of lactational exposure may, similarly to eVects of prenatal exposure, be counteracted or masked by optimal parental and home environmental conditions. In The Netherlands, comparable to most Western societies, the parents’ choice for breast‐feeding their child generally also reflects diVerences in, for example, levels of parental and home environmental conditions. Studies that explore subtle adverse eVects of lactational exposure to PCBs and dioxins may therefore benefit from more advanced modeling techniques in which the interrelationships of these neurodevelopmental determinants and exposure can be more properly modeled. Moreover, more insight is needed into potential beneficial eVects of breast‐feeding, such as

PCBS AND DIOXINS

73

the eVects of brain‐stimulating substances that are provided by breast milk and not by formula milk. The design and aims of the studies described in this paragraph are not adequate to address this aspect of breast‐feeding. However, the results of the neurophysiological study presented in this paragraph may suggest positive eVects of a longer duration of breast‐feeding in which potentially brain‐stimulating eVects of substances in breast milk are involved. Animal studies show evidence of profound neurodevelopmental eVects in monkeys that were exposed only to low levels of PCBs and dioxins through lactation (Rice, 1997, 1999; Rice & Hayward, 1997, 1999). These results indicate the potential for neurodevelopmental eVects of lactational exposure to PCBs and dioxins in humans. Moreover, these behavioral deficits in animals were suggestive of prefrontal cortex involvement. Since structure‐ related eVects of lactational exposure can be hypothesized considering maturation diVerences of brain structures, risk assessment studies that address lactational exposure should include a more elaborate neuropsychological test battery and larger study populations in which children were breast‐fed for longer durations than in the Dutch cohort (median of breast‐feeding duration 16 weeks). This may increase the knowledge of neurotoxic eVects of lactational exposure as well as help to diVerentiate eVects of prenatal and lactational exposure to PCBs and dioxins. Although infants are exposed to relatively large amounts of PCBs and dioxins through lactation, neurodevelopmental eVects of prenatal exposure to environmental levels of PCBs and dioxins were generally more pronounced. Subtle eVects of postnatal exposure to PCBs and dioxins were detected on one of the neurodevelopmental outcome variables that were explored in the Dutch PCB/dioxin cohort. On the other hand, the neurophysiological data may suggest beneficial eVects of a longer duration of breast‐ feeding in which potentially brain‐stimulating eVects of substances in breast milk are involved. These results do not warrant restrictions on breast‐feeding or reductions of the period of breast‐feeding in the Western societies. Neurodevelopmental eVects of lactational exposure to PCBs and dioxins and eVects of breast milk brain‐stimulating substances should be studied more thoroughly, using advanced modeling techniques in addition to addressing specific cognitive domains in larger cohorts as well as animal research. C.

Magnitude of Estimated Neurodevelopmental Effects

The magnitude of neurodevelopmental eVects that were associated with PCBs and dioxin exposure is relatively small in the Dutch cohort, and is not likely to be clinically relevant to the individual child. The level of cognitive development from 3 to 84 months of age, for example, in children born to

74

Hestien J. I. Vreugdenhil and Nynke Weisglas-Kuperus

younger mothers, was approximately 3 points lower in high prenatally exposed children (75% equivalent) compared to their low-exposed counterparts (25% equivalent). Under less favorable parental and home environmental conditions, however, the magnitude of cognitive and motor decrements may be larger. The Rotterdam cohort consists of families willing to participate for at least 7 years in this study. Parental and home environmental characteristics of this group are therefore likely to be more advantaged than in the average Dutch population or in populations in which educational possibilities or potential for cognitive stimulation are limited. When considering these subtle eVects in a large population, a lower average IQ shifts the distribution and increases the number of individuals who can be classified as retarded (IQ < 85). Additionally, it decreases the number of gifted and exceptionally gifted individuals (IQ > 130). For example, if the average IQ is shifted by 5 points (in a normal distribution with a mean of 100 and a standard deviation of 15), the number of children that score below 70 increases by a factor of 2 (Rice, 1998b). Neurodevelopmental eVects of perinatal exposure to PCBs and dioxins are detectable in a cohort of normal children. The magnitude of the eVects is relatively small and not likely to be clinically relevant to the individual child. The magnitude of neurodevelopmental eVects may be somewhat larger in populations in which conditions for child development are less favorable. For the whole society, however, these subtle decrements may have long‐term consequences.

VII.

FUTURE PERSPECTIVES

The epidemiological PCB studies described in this chapter draw attention to a number of important aspects that should be considered in this type of prospective follow‐up risk assessment studies that address eVects of perinatal exposure to PCBs and dioxins on neurodevelopmental outcome. First, the results of these studies may illustrate the importance of nonrandom attrition of the subjects of the original cohort. Ten percent of the original cohort was lost to follow‐up at school age. Although exposure levels were not statistically diVerent between participating and nonparticipating children, the latter group was significantly more formula‐fed, breast‐fed for shorter periods, and maternal age, parental education level, and verbal IQ were significantly lower in this lost to follow‐up group. Since developmental eVects of prenatal exposure to PCBs and dioxins may be influenced by parental and home environmental conditions, this is an important change in the study population. At preschool age, adverse eVects of prenatal PCB

PCBS AND DIOXINS

75

exposure on cognitive development were seen in the total cohort, whereas at school age, significant adverse eVects were seen only when parental and home characteristics were less optimal. The higher mean levels of these background variables in the population at school age might explain that no eVect of prenatal PCB exposure was seen in the total cohort, adjusting for the mean population levels of the confounders. Therefore, changes in the distribution of these variables in a cohort are a point of great attention in prospective follow‐up studies that address neurodevelopmental risks of perinatal exposure to PCBs and dioxins, since it may cause missing neurodevelopmental eVects in older children. Second, the choice of neurodevelopmental outcomes to detect adverse eVects of prenatal and lactational exposure to PCBs and dioxins should be addressed with great care in risk assessment studies. For example, general cognitive abilities, as measured with developmental tests, may not be the most sensitive outcome to detect neurotoxic eVects of lactational exposure to PCBs and dioxins since this outcome is particularly sensitive to parental and home environmental conditions. The process of learning or more specific neuropsychological functions as well as motor development may be more sensitive outcomes in risk assessment studies addressing subtle eVects of lactational exposure to neurotoxicants. Third, due to the complex interrelationships of various neurodevelopmental determinants and maternal PCB and dioxin levels, risk assessment studies may benefit from using sophisticated statistical modeling techniques. Moreover, these analyses make it possible to address the developmental course of functions in addition to addressing the level of functions at a certain point during the development of those functions. Fourth, due to diVerences in eating habits or area diVerences in environmental PCB and dioxin mixtures, populations worldwide are exposed to dissimilar mixtures of PCBs and dioxins. For example, results from the Oswego Study indicated that the cord blood of women who consumed Lake Ontario fish contained a significantly higher proportion of the most heavily chlorinated PCBs relative to non‐fish eaters. Levels of PCBs of lighter chlorination as well as the total PCB levels were similar in these groups (Stewart et al., 1999). Moreover, the cord blood levels of the highly chlorinated PCBs correlated more strongly with breast milk PCB levels than lower chlorinated PCBs. The results of the neurodevelopmental analyses in this cohort (children from birth to 12 months of age) showed some evidence of more pronounced neurodevelopmental eVects of exposure to the higher chlorinated PCBs (Darvill et al., 2000). The initial findings of this study as well as the results of laboratory studies therefore suggest that risk assessment studies can benefit from addressing more thoroughly the eVects of diVerent types of congeners to which children are exposed.

76

Hestien J. I. Vreugdenhil and Nynke Weisglas-Kuperus

Fifth, environmental levels of PCBs and dioxins are generally declining, due to worldwide control of sources, regulations of disposal practices, elimination of production, and natural attenuation. In The Netherlands, eVorts to minimize dioxin emissions, as were performed from the late 1980s, clearly show decreasing levels of PCBs and dioxins in food in the past 10 years (Liem et al., 2000). In breast milk, dioxin levels even decreased up to 50% during the past decade (Liem et al., 2000; Van Leeuwen & Malisch, 2002) (see Fig. 2). Children, however, are perinatally exposed to a large number of other potentially neurotoxic-persistent environmental pollutants such as heavy metals, pesticides and insecticides, flame retardants, and cleansers. For example, although breast milk levels of PCBs and dioxins have decreased over the past years, an increase is seen in the levels of another group of persistent organic pollutants, polybrominated diphenyl ethers (PBDEs) (Meironyte et al., 1999). PBDEs are used as flame retardants and are presently applied throughout the world. The chemical structure of the PBDEs resembles the structure of PCBs and dioxins and their neurotoxic properties have been recognized (Darnerud et al., 2001). Furthermore, of the over 80,000 chemicals that are used in commerce and industry, only a small proportion has undergone testing for neurodevelopmental toxicity. PCBs and dioxins are among the few contaminants subjected to extensive research exploring their neurotoxic properties and neurodevelopmental consequences for humans exposed to environmental levels of these compounds. The subtle neurodevelopmental decrements detected in the prospective follow‐up studies in healthy‐born children who were perinatally exposed to relatively low levels, environmental levels of PCBs and dioxins may be illustrative for the

FIG. 2. Temporal trends of levels of PCDD/PCDF in human milk (Van Leeuwen & Malisch, 2002).

PCBS AND DIOXINS

77

potential risks of exposure to other manmade neurotoxic compounds. These environmental contaminants deserve serious consideration since ‘‘...the ultimate pollution is the chemical contamination of the brain, mind, and intelligence’’ (Muir & Zegarac, 2001). REFERENCES Alarcon, M., Plomin, R., Fulker, D. W., Corley, R., & DeFries, J. C. (1998). Multivariate path analysis of specific cognitive abilities data at 12 years of age in the Colorado Adoption Project. Behavioural Genetics, 28, 255–264. Altmann, L., Weinand‐Haerer, A., Lilienthal, H., & Wiegand, H. (1995). Maternal exposure to polychlorinated biphenyls inhibits long‐term potentiation in the visual cortex of adult rats. Neuroscience Letters, 202, 53–56. Amin, S., Moore, R. W., Peterson, R. E., & Schantz, S. L. (2000). Gestational and lactational exposure to TCDD or coplanar PCBs alters adult expression of saccharin preference behavior in female rats. Neurotoxicology and Teratology, 22, 675–682. Anderson, J. W., Johnstone, B. M., & Remley, D. T. (1999). Breast‐feeding and cognitive development: A meta‐analysis. American Journal of Clinical Nutrition, 70, 525–535. Barkovich, A. J., & Kjos, B. O. (1988). Normal postnatal development of the corpus callosum as demonstrated by MR imaging. American Journal of Neuroradiology, 9, 487–491. Barkovich, A. J., Kjos, B. O., Jackson, D. E., Jr., & Norman, D. (1988). Normal maturation of the neonatal and infant brain: MR imaging at 1.5 T. Radiology, 166, 173–180. Becker, L. E., Armstrong, D. L., Chan, F., & Wood, M. M. (1984). Dendritic development in human occipital cortical neurons. Brain Research, 315, 117–124. Bellinger, D., Leviton, A., Waternaux, C., Needleman, H., & Rabinowitz, M. (1988). Low‐level lead exposure, social class, and infant development. Neurotoxicology and Teratology, 10, 497–503. Bitman, J., & Cecil, H. C. (1970). Estrogenic activity of DDT analogs and polychlorinated biphenyls. Journal of Agriculture Food Chemistry, 18, 1108–1112. Bowman, R. E., Heironimus, M. P., & Allen, J. R. (1978). Correlation of PCB body burden with behavioral toxicology in monkeys. Pharmacology Biochemistry and Behavior, 9, 49–56. Bradley, R. H., Convyn, R. F., Burchinal, M., McAdoo, H. P., & Coll, C. G. (2001). The home environments of children in the United States part II: Relations with behavioral development through age thirteen. Child Development, 72, 1868–1886. Brenner, E., Mirmiran, M., Uylings, H. B., & Van der Gugten, J. (1985). Growth and plasticity of rat cerebral cortex after central noradrenaline depletion. Experimantal Neurology, 89, 264–268. Brouwer, A., Ahlborg, U. G., Van den Berg, M., Birnbaum, L. S., Boersma, E. R., Bosveld, B., Denison, M. S., Gray, L. E., Hagmar, L., Holene, E., Huisman, M., Jacobson, S., Jacobson, J. L., Koopman‐Esseboom, C., Koppe, J. G., Kulig, B. M., Prooije, A. E., Touwen, B. C. L., Weisglas‐Kuperus, N., & Winneke, G. (1995). Functional aspects of developmental toxicity of polyhalogenated aromatic hydrocarbons in experimental animals and human infants. European Journal of Pharmacology, 293, 1–40. Brouwer, A., Longnecker, M. P., Birnbaum, L. S., Cogliano, J., Kostyniak, P., Moore, J., Schantz, S., & Winneke, G. (1999). Characterization of potential endocrine‐related health eVects at low‐dose levels of exposure to PCBs. Environmental Health Perspectives, 107(Suppl. 4), 639–649.

78

Hestien J. I. Vreugdenhil and Nynke Weisglas-Kuperus

Brouwer, A., Morse, D. C., Lans, M. C., Schuur, A. G., Murk, A. J., Klasson‐Wehler, E., Bergman, A., & Visser, T. J. (1998). Interactions of persistent environmental organohalogens with the thyroid hormone system: Mechanisms and possible consequences for animal and human health. Toxicology of Industrial Health, 14, 59–84. Burse, V. W., Korver, M. P., Needham, L. L., Lapeza, C. R., Jr., Boozer, E. L., Head, S. L., Liddle, J. A., & Bayse, D. D. (1989). Gas chromatographic determination of polychlorinated biphenyls (as Aroclor 1254) in serum: Collaborative study. Journal of the Association of Analytical Chemistry, 72, 649–659. Chen, Y. C., Guo, Y. L., Hsu, C. C., & Rogan, W. J. (1992). Cognitive development of Yu‐ Cheng (‘‘oil disease’’) children prenatally exposed to heat‐degraded PCBs. Journal of the American Medical Association, 268, 3213–3218. Chen, Y. J., & Hsu, C. C. (1994). EVects of prenatal exposure to PCBs on the neurological function of children: A neuropsychological and neurophysiological study. Developmental Medicine and Child Neurology, 36, 312–320. Chiron, C., Raynaud, C., Maziere, B., Zilbovicius, M., Laflamme, L., Masure, M. C., Dulac, O., Bourguignon, M., & Syrota, A. (1992). Changes in regional cerebral blood flow during brain maturation in children and adolescents. Journal of Nuclear Medicine, 33, 696–703. Chugani, H. T., Phelps, M. E., & Mazziotta, J. C. (1987). Positron emission tomography study of human brain functional development. Annals of Neurology, 22, 487–497. Darnerud, P. O., Eriksen, G. S., Johannesson, T., Larsen, P. B., & Viluksela, M. (2001). Polybrominated diphenyl ethers: Occurrence, dietary exposure, and toxicology. Environmental Health Perspectives, 109(Suppl. 1), 49–68. Darvill, T., Lonky, E., Reihman, J., Stewart, P., & Pagano, J. (2000). Prenatal exposure to PCBs and infant performance on the Fagan test of infant intelligence. Neurotoxicology, 21, 1029–1038. de Voogt, P., & Brinkman, U. A. T. (1989). Production, properties, and usage of polychlorinated biphenyls. In R. D. Kimbrough & A. Jensen (Eds.), Halogenated Biphenyls, Terphenyls, Naphthalenes, Dibenzodioxins, and Related Products (pp. 2–46). New York: Elsevier. Devoogd, T. J., Nixdorf, B., & Nottebohm, F. (1985). Synaptogenesis and changes in synaptic morphology related to acquisition of a new behavior. Brain Research, 329, 304–308. Diamond, M. C., Lindner, B., Johnson, R., Bennett, E. L., & Rosenzweig, M. R. (1975). DiVerences in occipital cortical synapses from environmentally enriched, impoverished, and standard colony rats. Journal of Neuroscience Research, 1, 109–119. Dodgson, M. C. H. (1962). The Growing Brain: An Essay in Developmental Neurology. London: Wright. Eriksson, P., Lundkvist, U., & Fredriksson, A. (1991). Neonatal exposure to 3,30 ,4,40 ‐ tetrachlorobiphenyl: Changes in spontaneous behavior and cholinergic muscarinic receptors in the adult mouse. Toxicology, 69, 27–34. Fischer, L. J., Seegal, R. F., Ganey, P. E., Pessah, I. N., & Kodavanti, P. R. (1998). Symposium overview: Toxicity of non‐coplanar PCBs. Toxicological Science, 41, 49–61. Fitch, R. H., & Denenberg, V. H. (1998). A role for ovarian hormones in sexual diVerentiation of the brain. Behavior and Brain Science, 21, 311–327; discussion 327–352. Furst, P., Beck, H., & Theelen, R. (1992). Assessment of human intake of PCDDs and PCDFs from diVerent environmental sources. Toxic Substances Journal, 12, 133–150. Giesy, J. P., & Kannan, K. (1998). Dioxin‐like and non‐dioxin‐like toxic eVects of polychlorinated biphenyls (PCBs): Implications for risk assessment. Critical Reviews in Toxicology, 28, 511–569. Gilbert, E. S., & Crowley, D. E. (1997). Plant compounds that induce polychlorinated biphenyl biodegradation by Arthrobacter sp. strain B1B. Applied Environmental Microbiology, 63, 1933–1938.

PCBS AND DIOXINS

79

Gladen, B. C., & Rogan, W. J. (1991). EVects of perinatal polychlorinated biphenyls and dichlorodiphenyl dichloroethene on later development. Journal of Pediatrics, 119, 58–63. Gladen, B. C., Rogan, W. J., Hardy, P., Thullen, J., Tingelstad, J., & Tully, M. (1988). Development after exposure to polychlorinated biphenyls and dichlorodiphenyl dichloroethene transplacentally and through human milk. Journal of Pediatrics, 113, 991–995. Golden, R. J., Noller, K. L., Titus‐ErnstoV, L., Kaufman, R. H., Mittendorf, R., Stillman, R., & Reese, E. A. (1998). Environmental endocrine modulators and human health: An assessment of the biological evidence. Critical Reviews of Toxicology, 28, 109–227. Goldman, P. S., Rosvold, H. E., Vest, B., & Galkin, T. W. (1971). Analysis of the delayed‐ alternation deficit produced by dorsolateral prefrontal lesions in the rhesus monkey. Journal of Comparative and Physiological Psychology, 77, 212–220. Golombok, S., & Rust, J. (1993). The Pre‐School Activity Inventory: A standardized assessment of gender role in children. Psychological Assessment, 5, 131–136. Grandjean, P., Weihe, P., Burse, V. W., Needham, L. L., Storr‐Hansen, E., Heinzow, B., Debes, F., Murata, K., Simonsen, H., Ellefsen, P., Budtz‐Jorgensen, E., Keiding, N., & White, R. F. (2001). Neurobehavioral deficits associated with PCB in 7‐year‐old children prenatally exposed to seafood neurotoxicants. Neurotoxicology and Teratology, 23, 305–317. Grandjean, P., Weihe, P., Jorgensen, P. J., Clarkson, T., Cernichiari, E., & Videro, T. (1992). Impact of maternal seafood diet on fetal exposure to mercury, selenium, and lead. Archives of Environmental Health, 47, 185–195. Grandjean, P., Weihe, P., Needham, L. L., Burse, V. W., Patterson, D. G., Jr., Sampson, E. J., Jorgensen, P. J., & Vahter, M. (1995). Relation of a seafood diet to mercury, selenium, arsenic, and polychlorinated biphenyl and other organochlorine concentrations in human milk. Environmental Research, 71, 29–38. Guo, Y. L., Lai, T. J., Chen, S. J., & Hsu, C. C. (1995). Gender‐related decrease in Raven’s progressive matrices scores in children prenatally exposed to polychlorinated biphenyls and related contaminants. Bulletin of Environmental Contaminents and Toxicology, 55, 8–13. Hany, J., Lilienthal, H., Sarasin, A., Roth‐Harer, A., Fastabend, A., Dunemann, L., Lichtensteiger, W., & Winneke, G. (1999). Developmental exposure of rats to a reconstituted PCB mixture or aroclor 1254: EVects on organ weights, aromatase activity, sex hormone levels, and sweet preference behavior. Toxicology and Applied Pharmacology, 158, 231–243. Harada, M. (1976). Intrauterine poisoning: Clinical and epidemiological studies and significance of the problem. Bulletin of the Institute of Constitutional Medicine of Kumamoto University, 25, 1–69. Huisman, M., Koopman‐Esseboom, C., Fidler, V., Hadders‐Algra, M., van der Paauw, C. G., Tuinstra, L. G., Weisglas‐Kuperus, N., Sauer, P. J., Touwen, B. C., & Boersma, E. R. (1995a). Perinatal exposure to polychlorinated biphenyls and dioxins and its eVect on neonatal neurological development. Early Human Development, 41, 111–127. Huisman, M., Koopman‐Esseboom, C., Lanting, C. I., van der Paauw, C. G., Tuinstra, L. G., Fidler, V., Weisglas‐Kuperus, N., Sauer, P. J., Boersma, E. R., & Touwen, B. C. (1995b). Neurological condition in 18‐month‐old children perinatally exposed to polychlorinated biphenyls and dioxins. Early Human Development, 43, 165–176. Huttenlocher, P. R., & Dabholkar, A. S. (1997). Regional diVerences in synaptogenesis in human cerebral cortex. Journal of Comparative Neurology, 387, 167–178. Innis, S. M. (1994). The 1993 Borden Award Lecture. Fatty acid requirements of the newborn. Canadian Journal of Physiology and Pharmacology, 72, 1483–1492. Jacobson, J. L., Fein, G. G., Jacobson, S. W., Schwartz, P. M., & Dowler, J. K. (1984). The transfer of polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs) across

80

Hestien J. I. Vreugdenhil and Nynke Weisglas-Kuperus

the human placenta and into maternal milk. American Journal of Public Health, 74, 378–379. Jacobson, J. L., & Jacobson, S. W. (1996). Intellectual impairment in children exposed to polychorinated biphenyls in utero. New England Journal of Medicine, 335, 783–789. Jacobson, J. L., & Jacobson, S. W. (2001). Developmental eVects of PCBs in the fish eater cohort studies. In L. W. Robertson & L. G. Hansen (Eds.), PCBs: Recent Advances in Environmental Toxicology and Health EVects (pp. 127–136). The University Press of Kentucky. Jacobson, J. L., Jacobson, S. W., Fein, G., Scwartz, P., & Dowler, J. (1984). Prenatal exposure to environmental toxin: A test of the multiple eVects model. Developmental Psychology, 20, 523–532. Jacobson, J. L., Jacobson, S. W., & Humphrey, H. E. (1990). EVects of in utero exposure to polychlorinated biphenyls and related contaminants on cognitive functioning in young children. Journal of Pediatrics, 116, 38–45. Jacobson, J. L., Jacobson, S. W., Padgett, R. T., Brumitt, G. A., & Billings, R. L. (1992). EVects of prenatal PCB exposure on cognitive processing eYciency and sustained attention. Developmental Psychology, 28, 297–306. Jansen, H. T., Cooke, P. S., Porcelli, J., Liu, T. C., & Hansen, L. G. (1993). Estrogenic and antiestrogenic actions of PCBs in the female rat: In vitro and in vivo studies. Reproductive Toxicology, 7, 237–248. Kafafi, S. A., Afeefy, H. Y., Ali, A. H., Said, H. K., & Kafafi, A. G. (1993). Binding of polychlorinated biphenyls to the aryl hydrocarbon receptor. Environmental Health Perspectives, 101, 422–428. Kester, M. H., Bulduk, S., Tibboel, D., Meinl, W., Glatt, H., Falany, C. N., Coughtrie, M. W., Bergman, A., Safe, S. H., Kuiper, G. G., Schuur, A. G., Brouwer, A., & Visser, T. J. (2000). Potent inhibition of estrogen sulfotransferase by hydroxylated PCB metabolites: A novel pathway explaining the estrogenic activity of PCBs. Endocrinology, 141, 1897–1900. Kodavanti, P. R., Shafer, T. J., Ward, T. R., Mundy, W. R., Freudenrich, T., Harry, G. J., & Tilson, H. A. (1994). DiVerential eVects of polychlorinated biphenyl congeners on phosphoinositide hydrolysis and protein kinase C translocation in rat cerebellar granule cells. Brain Research, 662, 75–82. Kodavanti, P. R., Shin, D. S., Tilson, H. A., & Harry, G. J. (1993). Comparative eVects of two polychlorinated biphenyl congeners on calcium homeostasis in rat cerebellar granule cells. Toxicology and Applied Pharmacology, 123, 97–106. Kodavanti, P. R., & Tilson, H. A. (1997). Structure‐activity relationships of potentially neurotoxic PCB congeners in the rat. Neurotoxicology, 18, 425–441. Kolb, B. (1989). Brain development, plasticity, and behavior. American Psychologist, 44, 1203–1212. Koopman‐Esseboom, C., Huisman, M., Weisglas‐Kuperus, N., Van der Pauw, C. G., Tuinstra, L. G. M. T., Boersma, E. R., & Sauer, P. J. (1994a). PCB and dioxin levels in plasma and human milk of 418 Dutch women and their infants. Predictive value of PCB congener levels in maternal plasma for fetal and infant’s exposure to PCBs and dioxins. Chemosphere, 28, 1721–1732. Koopman‐Esseboom, C., Morse, D. C., Weisglas‐Kuperus, N., Lutkeschipholt, I. J., Van der Paauw, C. G., Tuinstra, L. G., Brouwer, A., & Sauer, P. J. (1994b). EVects of dioxins and polychlorinated biphenyls on thyroid hormone status of pregnant women and their infants. Pediatric Research, 36, 468–473. Koopman‐Esseboom, C., Weisglas‐Kuperus, N., de Ridder, M. A., Van der Paauw, C. G., Tuinstra, L. G., & Sauer, P. J. (1996). EVects of polychlorinated biphenyl/ dioxin exposure and feeding type on infants’ mental and psychomotor development. Pediatrics, 97, 700–706.

PCBS AND DIOXINS

81

Korach, K. S., Sarver, P., Chae, K., McLachlan, J. A., & McKinney, J. D. (1988). Estrogen receptor‐binding activity of polychlorinated hydroxybiphenyls: Conformationally restricted structural probes. Molecular Pharmacology, 33, 120–126. Kramer, V. J., Helferich, W. G., Bergman, A., Klasson‐Wehler, E., & Giesy, J. P. (1997). Hydroxylated polychlorinated biphenyl metabolites are anti‐estrogenic in a stably transfected human breast adenocarcinoma (MCF7) cell line. Toxicology and Applied Pharmacology, 144, 363–376. Lai, T. J., Guo, Y. L., Yu, M. L., Ko, H. C., & Hsu, C. C. (1994). Cognitive development in Yucheng children. Chemosphere, 29, 2405–2411. Landry, S. H., Denson, S. E., & Swank, P. R. (1997). EVects of medical risk and socioeconomic status on the rate of change in cognitive and social development for low birth weight children. Journal of Clinical Experimental Neuropsychology, 19, 261–274. Lanting, C. I., Huisman, M., Muskiet, F. A., van der Paauw, C. G., Essed, C. E., & Boersma, E. R. (1998a). Polychlorinated biphenyls in adipose tissue, liver, and brain from nine stillborns of varying gestational ages. Pediatric Research, 44, 222–225. Lanting, C. I., Patandin, S., Fidler, V., Weisglas‐Kuperus, N., Sauer, P. J., Boersma, E. R., & Touwen, B. C. (1998b). Neurological condition in 42‐month‐old children in relation to pre‐ and postnatal exposure to polychlorinated biphenyls and dioxins. Early Human Development, 50, 283–292. Levin, E. D., Schantz, S. L., & Bowman, R. E. (1988). Delayed spatial alternation deficits resulting from perinatal PCB exposure in monkeys. Archives of Toxicology, 62, 267–273. Liem, A. K., Furst, P., & Rappe, C. (2000). Exposure of populations to dioxins and related compounds. Food Additives and Contaminants, 17, 241–259. Longnecker, M. P., WolV, M. S., Gladen, B. C., Brock, J. W., Grandjean, P., Jacobson, J. L., Korrick, S. A., Rogan, W. J., Weisglas‐Kuperus, N., Hertz‐Picciotto, I., Ayotte, P., Stewart, P., Winneke, G., Charles, M. J., Jacobson, S. W., Dewailly, E., Boersma, E. R., Altshul, L. M., Heinzow, B., Pagano, J. J., & Jensen, A. A. (2003). Comparison of polychlorinated biphenyl (PCB) levels across studies of human neurodevelopment. Environmental Health Perspectives, 111, 65–70. Lonky, E., Reihman, J., Darvill, T., Mather, J. E., & Daly, H. (1996). Neonatal Behavioral Assessment Scale performance in humans influenced by maternal consumption of environmentally contaminated Lake Ontario fish. Journal of Great Lakes, 22, 198–212. Mariussen, E., Andersson, P. L., Tysklind, M., & Fonnum, F. (2001). EVect of polychlorinated biphenyls on the uptake of dopamine into rat brain synaptic vesicles: A structure–activity study. Toxicology and Applied Pharmacology, 175, 176–183. Mariussen, E., & Fonnum, F. (2001). The eVect of polychlorinated biphenyls on the high aYnity uptake of the neurotransmitters, dopamine, serotonin, glutamate, and GABA, into rat brain synaptosomes. Toxicology, 159, 11–21. Mariussen, E., Morch Andersen, J., & Fonnum, F. (1999). The eVect of polychlorinated biphenyls on the uptake of dopamine and other neurotransmitters into rat brain synaptic vesicles. Toxicology and Applied Pharmacology, 161, 274–282. Masuda, Y., Kagawa, R., Kuroki, H., Kuratsune, M., Yoshimura, T., Taki, I., Kusuda, M., Yamashita, F., & Hayashi, M. (1978). Transfer of polychlorinated biphenyls from mothers to fetuses and infants. Food and Cosmetics Toxicology, 16, 543–546. Matsumoto, A. (1991). Synaptogenic action of sex steroids in developing and adult neuroendocrine brain. Psychoneuroendocrinology, 16, 25–40. McNaughton, B. L. (1993). The mechanism of expression of long‐term enhancement of hippocampal synapses: Current issues and theoretical implications. Annual Review of Physiology, 55, 375–396.

82

Hestien J. I. Vreugdenhil and Nynke Weisglas-Kuperus

Meironyte, D., Noren, K., & Bergman, A. (1999). Analysis of polybrominated diphenyl ethers in Swedish human milk. A time‐related trend study, 1972–1997. Journal of Toxicology and Environmental Health A, 58, 329–341. Mele, P. C., Bowman, R. E., & Levin, E. D. (1986). Behavioral evaluation of perinatal PCB exposure in rhesus monkeys: Fixed‐interval performance and reinforcement‐omission. Neurobehavioral Toxicology and Teratology, 8, 131–138. Moore, M., Mustain, M., Daniel, K., Chen, I., Safe, S., Zacharewski, T., Gillesby, B., Joyeux, A., & Balaguer, P. (1997). Antiestrogenic activity of hydroxylated polychlorinated biphenyl congeners identified in human serum. Toxicology and Applied Pharmacology, 142, 160–168. Morse, D. C., Plug, A., Wesseling, W., van den Berg, K. J., & Brouwer, A. (1996a). Persistent alterations in regional brain glial fibrillary acidic protein and synaptophysin levels following pre‐ and postnatal polychlorinated biphenyl exposure. Toxicology and Applied Pharmacology, 139, 252–261. Morse, D. C., Seegal, R. F., Borsch, K. O., & Brouwer, A. (1996b). Long‐term alterations in regional brain serotonin metabolism following maternal polychlorinated biphenyl exposure in the rat. Neurotoxicology, 17, 631–638. Moser, M. B., Trommald, M., & Andersen, P. (1994). An increase in dendritic spine density on hippocampal CA1 pyramidal cells following spatial learning in adult rats suggests the formation of new synapses. Proceedings of the National Academy of Science USA, 91, 12673–12675. Mrzljak, L., Uylings, H. B., Van Eden, C. G., & Judas, M. (1990). Neuronal development in human prefrontal cortex in prenatal and postnatal stages. Progress in Brain Research, 85, 185–222. Muir, T., & Zegarac, M. (2001). Societal costs of exposure to toxic substances: Economic and health costs of four case studies that are candidates for environmental causation. Environmental Health Perspectives, 109(Suppl. 6), 885–903. Niemi, W. D., Audi, J., Bush, B., & Carpenter, D. O. (1998). PCBs reduce long‐term potentiation in the CA1 region of rat hippocampus. Experimental Neurology, 151, 26–34. Overmann, S. R., Kostas, J., Wilson, L. R., Shain, W., & Bush, B. (1987). Neurobehavioral and somatic eVects of perinatal PCB exposure in rats. Environmental Research, 44, 56–70. Patandin, S., Dagnelie, P. C., Mulder, P. G., Op de Coul, E., van der Veen, J. E., Weisglas‐ Kuperus, N., & Sauer, P. J. (1999a). Dietary exposure to polychlorinated biphenyls and dioxins from infancy until adulthood: A comparison between breast‐feeding, toddler, and long‐term exposure [see comments]. Environmental Health Perspectives, 107, 45–51. Patandin, S., Lanting, C. I., Mulder, P. G., Boersma, E. R., Sauer, P. J., & Weisglas‐Kuperus, N. (1999b). EVects of environmental exposure to polychlorinated biphenyls and dioxins on cognitive abilities in Dutch children at 42 months of age [see comments]. Journal of Pediatrics, 134, 33–41. Patandin, S., Veenstra, J., Mulder, P. G. H., Sewnaik, A., Sauer, P. J. J., & Weisglas‐Kuperus, N. (1999c). Attention and activity in 42‐month‐old Dutch children with environmental exposure to polychlorinated biphenyls and dioxins. In EVects of Environmental Exposure to Polychlorinated Biphenyls and Dioxins on Growth and Development in Young Children; Doctoral Thesis (pp. 123–142). Patandin, S., Weisglas‐Kuperus, N., de Ridder, M. A., Koopman‐Esseboom, C., van Staveren, W. A., van der Paauw, C. G., & Sauer, P. J. (1997). Plasma polychlorinated biphenyl levels in Dutch preschool children either breast‐fed or formula‐fed during infancy. American Journal of Public Health, 87, 1711–1714. PfeiVer, S. I., & Aylward, G. P. (1990). Outcome for preschoolers of very low birthweight: Sociocultural and environmental influences. Perceptual and Motor Skills, 70, 1367–1378.

PCBS AND DIOXINS

83

Plomin, R., & Loehlin, J. C. (1989). Direct and indirect IQ heritability estimates: A puzzle. Behavioral Genetics, 19, 331–342. Porterfield, S. P. (1994). Vulnerability of the developing brain to thyroid abnormalities: Environmental insults to the thyroid system. Environmental Health Perspectives, 102, 125–130. Posthuma, D., de Geus, E. J., & Boomsma, D. I. (2001). Perceptual speed and IQ are associated through common genetic factors. Behavioral Genetics, 31, 593–V602. Rice, D. C. (1988). Schedule‐controlled behavior in infant and juvenile monkeys exposed to lead from birth. Neurotoxicology, 9, V75–V87. Rice, D. C. (1995). Neurotoxicity of lead, methylmercury, and PCBs in relation to the Great Lakes. Environmental Health Perspectives, 103(Suppl. 9), V71–V87. Rice, D. C. (1997). EVect of postnatal exposure to a PCB mixture in monkeys on multiple fixed interval‐fixed ratio performance. Neurotoxicology and Teratology, 19, 429–434. Rice, D. C. (1998a). EVects of postnatal exposure of monkeys to a PCB mixture on spatial discrimination reversal and DRL performance. Neurotoxicology and Teratology, 20, 391–400. Rice, D. C. (1998b). Issues in developmental neurotoxicology: Interpretation and implications of the data. Canadian Journal of Public Health, 89(Suppl. 1), S31–S36, S34–S40. Rice, D. C. (1999). Behavioral impairment produced by low‐level postnatal PCB exposure in monkeys. Environmental Research, 80, S113–S121. Rice, D. C., & Hayward, S. (1997). EVects of postnatal exposure to a PCB mixture in monkeys on nonspatial discrimination reversal and delayed alternation performance. Neurotoxicology, 18, 479–494. Rice, D. C., & Hayward, S. (1999). EVects of postnatal exposure of monkeys to a PCB mixture on concurrent random interval–random interval and progressive ratio performance. Neurotoxicology and Teratology, 21, 47–58. Rogan, W. J., & Gladen, B. C. (1991). PCBs, DDE, and child development at 18 and 24 months. Annals of Epidemiology, 1, 407–413. Rogan, W. J., Gladen, B. C., McKinney, J. D., Carreras, N., Hardy, P., Thullen, J., Tingelstad, J., & Tully, M. (1986a). Polychlorinated biphenyls (PCBs) and dichlorodiphenyl dichloroethene (DDE) in human milk: EVects of maternal factors and previous lactation. American Journal of Public Health, 76, 172–177. Rogan, W. J., Gladen, B. C., McKinney, J. D., Carreras, N., Hardy, P., Thullen, J., Tinglestad, J., & Tully, M. (1986b). Neonatal eVects of transplacental exposure to PCBs and DDE. Journal of Pediatrics, 109, 335–341. Rosenzweig, M. R., & Bennett, E. L. (1996). Psychobiology of plasticity: EVects of training and experience on brain and behavior. Behavioral Brain Research, 78, 57–65. Rovet, J. F., & Ehrlich, R. M. (1995). Long‐term eVects of L‐thyroxine therapy for congenital hypothyroidism. Journal of Pediatrics, 126, 380–386. Safe, S. (1990). Polychlorinated biphenyls (PCBs), dibenzo‐p‐dioxins (PCDDs), dibenzofurans (PCDFs), and related compounds: Environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs). Critical Reviews in Toxicology, 21, 51–88. Safe, S., & Goldstein, J. A. (1989). Mechanisms of action and structure‐activity relationships for the chlorinated dibenzo‐p‐dioxins and related compounds. In R. D. Kimbrough & A. Jensen (Eds.), Halogenated Biphenyls, Terphenyls, Naphtalenes, Dibenzodioxins, and Related Products (pp. 239–294). New York: Elsevier. Safe, S. H. (1994). Polychlorinated biphenyls (PCBs): Environmental impact, biochemical and toxic responses, and implications for risk assessment. Critical Reviews in Toxicology, 24, 87–149.

84

Hestien J. I. Vreugdenhil and Nynke Weisglas-Kuperus

Saper, C. B., Iversen, S., & Frackowiak, R. S. (2000). The association areas of the cerebral cortex and the cognitive capacities of the brain. In E. R. Kandell, J. H. Schwartz, & T. M. Jessel (Eds.), Principles of Neural Science (p. 361). New York: McGraw-Hill. Schantz, S. L., Levin, E. D., & Bowman, R. E. (1991). Long‐term neurobehavioral eVects of perinatal polychlorinated biphenyl (PCB) exposure in monkeys. Environmental Toxicology and Chemistry, 10, 747–756. Schantz, S. L., Levin, E. D., Bowman, R. E., Heironimus, M. P., & Laughlin, N. K. (1989). EVects of perinatal PCB exposure on discrimination‐reversal learning in monkeys. Neurotoxicology and Teratology, 11, 243–250. Seegal, R. F., Brosch, K. O., & Okoniewski, R. J. (1997). EVects of in utero and lactational exposure of the laboratory rat to 2,4,20 ,40 ‐ and 3,4,30 ,40 ‐tetrachlorobiphenyl on dopamine function. Toxicology and Applied Pharmacology, 146, 95–103. Shafer, T. J., Mundy, W. R., Tilson, H. A., & Kodavanti, P. R. (1996). Disruption of inositol phosphate accumulation in cerebellar granule cells by polychlorinated biphenyls: A consequence of altered Ca2þ homeostasis. Toxicology and Applied Pharmacology, 141, 448–455. Shain, W., Bush, B., & Seegal, R. (1991). Neurotoxicity of polychlorinated biphenyls: Structure‐ activity relationship of individual congeners. Toxicology and Applied Pharmacology, 111, 33–42. Steele, G., Stehr‐Green, P., & Welty, E. (1986). Estimates of the biologic half‐life of polychlorinated biphenyls in human serum. New England Journal of Medicine, 314, 926–927. Stein, Z. A. (1985). A woman’s age: Childbearing and child rearing. American Journal of Epidemiology, 121, 327–342. Stewart, P., Darvill, T., Lonky, E., Reihman, J., Pagano, J., & Bush, B. (1999). Assessment of prenatal exposure to PCBs from maternal consumption of Great Lakes fish: An analysis of PCB pattern and concentration. Environmental Research, 80, S87–S96. Tanabe, S. (1988). PCB problems in the future: Foresight from current knowledge. Environmental Pollution, 50, 5–28. Taylor, P. R., & Lawrence, C. E. (1992). Polychlorinated biphenyls: Estimated serum half lives. British Journal of Industrial Medicine, 49, 527–528. Thiel, R., Koch, E., Ulbrich, B., & Chahoud, I. (1994). Peri‐ and postnatal exposure to 2,3,7,8‐ tetrachlorodibenzo‐p‐dioxin: EVects on physiological development, reflexes, locomotor activity, and learning behavior in Wistar rats. Archives of Toxicology, 69, 79–86. Tilson, H. A., Davis, G. J., McLachlan, J. A., & Lucier, G. W. (1979). The eVects of polychlorinated biphenyls given prenatally on the neurobehavioral development of mice. Environmental Research, 18, 466–474. Tilson, H. A., & Kodavanti, P. R. (1997). Neurochemical eVects of polychlorinated biphenyls: An overview and identification of research needs. Neurotoxicology, 18, 727–743. Tilson, H. A., & Kodavanti, P. R. (1998). The neurotoxicity of polychlorinated biphenyls. Neurotoxicology, 19, 517–525. Van den Berg, M., Birnbaum, L., Bosveld, A. T., Brunstrom, B., Cook, P., Feeley, M., Giesy, J. P., Hanberg, A., Hasegawa, R., Kennedy, S. W., Kubiak, T., Larsen, J. C., van Leeuwen, F. X., Liem, A. K., Nolt, C., Peterson, R. E., Poellinger, L., Safe, S., Schrenk, D., Tillitt, D., Tysklind, M., Younes, M., Waern, F., & Zacharewski, T. (1998a). Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environmental Health Perspectives, 106, 775–792. Van den Berg, M., Birnbaum, L., Bosveld, A. T. C., Brunstrom, B., Cook, P., Feeley, M., Giesy, J. P., Hanberg, A., Hasegawa, R., Kennedy, S. W., Kubiak, T., Larsen, J. C., van

PCBS AND DIOXINS

85

Leeuwen, F. X., Liem, A. K., Nolt, C., Peterson, R. E., Poellinger, L., Safe, S., Schrenk, D., Tillitt, D., Tysklind, M., Younes, M., Waern, F., & Zacharewski, T. (1998b). Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife [see comments]. Environmemtal Health Perspectives, 106, 775–792. Van der Meulen, B. F., & Smirkovsky, M. (1985). Mos. 2 1/2 –8 1/2 McCarthy Ontwikkelingsschalen. The Netherlands: Swets & Zeitlinger B.V. Van Leeuwen, F. X. R., & Malisch, R. (2002). Results of the third round of the WHO‐ coordinated exposure study on the levels of PCBs, PCDDs, and PCDFs in human milk. Organohalogen Compounds, 56, 311–316. Vreugdenhil, H. J., Lanting, C. I., Mulder, P. G., Boersma, E. R., & Weisglas‐Kuperus, N. (2002a). EVects of prenatal PCB and dioxin background exposure on cognitive and motor abilities in Dutch children at school age. Journal of Pediatrics, 140, 48–56. Vreugdenhil, H. J., Slijper, F. M., Mulder, P. G., & Weisglas‐Kuperus, N. (2002b). EVects of perinatal exposure to PCBs and dioxins on play behavior in Dutch children at school age. Environmental Health Perspectives, 110, A593–A598. Vreugdenhil, H. J. I., Duivenvoorden, H. J., & Weisglas‐Kuperus, N. (2002c). Neurodevelopmental EVects of Perinatal Exposure to Environmental Levels of PCBs and Dioxins in Children at School Age. Rotterdam, the Netherlands: Erasmus University Thesis. Vreugdenhil, H. J. I., Mulder, P. G., Emmen, H. H., & Weisglas‐Kuperus, N. (2004a). EVects of perinatal exposure to PCBs on neuropsychological functions in the Rotterdam cohort at 9 years of age. Neuropsychology, 18, 185–193. Vreugdenhil, H. J. I., Van Zanten, G. A., Brocaar, M. P., Mulder, P. G. H., & Weisglas‐ Kuperus, N. (2004b). Prenatal PCB exposure and breast‐feeding aVect auditory P300 latencies in 9‐year‐old Dutch children. Developmental Medicine and Child Neurology, 46, 398–405. Walkowiak, J., Wiener, J. A., Fastabend, A., Heinzow, B., Kramer, U., Schmidt, E., Steingruber, H. J., Wundram, S., & Winneke, G. (2001). Environmental exposure to polychlorinated biphenyls and quality of the home environment: EVects on psychodevelopment in early childhood. Lancet, 358, 1602–1607. Weisglas‐Kuperus, N., Baerts, W., Smrkovsky, M., & Sauer, P. J. (1993). EVects of biological and social factors on the cognitive development of very low birth weight children. Pediatrics, 92, 658–665. Weisglas‐Kuperus, N., Patandin, S., Berbers, G. A., Sas, T. C., Mulder, P. G., Sauer, P. J., & Hooijkaas, H. (2000). Immunologic eVects of background exposure to polychlorinated biphenyls and dioxins in Dutch preschool children. Environmental Health Perspectives, 108, 1203–1207. WHO (1989). Levels of PCBs, PCDDs, and PCDFs in breast milk: Results of the WHO‐ coordinated interlaboratory quality control studies and analytical field studies. Environmental Health Series, 34. Winneke, G., Bucholski, A., Heinzow, B., Kramer, U., Schmidt, E., Walkowiak, J., Wiener, J. A., & Steingruber, H. J. (1998). Developmental neurotoxicity of polychlorinated biphenyls (PCBS): Cognitive and psychomotor functions in 7‐month‐old children. Toxicology Letters, 102–103, 423–428. Winneke, G., & Kraemer, U. (1984). Neuropsychological eVects of lead in children: Interactions with social background variables. Neuropsychobiology, 11, 195–202. WolV, J. R., Laskawi, R., Spatz, W. B., & Missler, M. (1995). Structural dynamics of synapses and synaptic components. Behavioural Brain Research, 66, 13–20.