Environmental Health Perspectives 103, Supplement 2, March 1995

Workshop on Perinatal Exposure to Dioxin-like Compounds

Gunilla Lindström,¹ Kim Hooper,¹ Myrto Petreas,¹ Robert Stephens,¹ Andrew Gilman²

¹Hazardous Materials Laboratory, Cal EPA, Berkeley, California;
²Bureau of Chemical Hazards, Health and Welfare Canada, Ottawa, Ontario, Canada

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Abstract
An international workshop reviewed 20 ongoing or recently completed studies of the effects of perinatal exposures to dioxins, dibenzofurans, and PCBs on the reproductive, endocrine, neurodevelopmental, and immune systems. Many of the observed effects are consistent with these compounds acting as "environmental hormones" or endocrine disrupters. This report summarizes the conclusions and future directions described at the workshop. -- Environ Health Perspect 103(Suppl 2):135-142 (1995)

Key words: PCB, PCDD, PCDF, perinatal, transplacental, lactational, reproduction, endocrinology, neurobehavior, immunology

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This paper summarizes issues discussed at the Workshop on Perinatal Exposure to Dioxin-like Compounds held 13-15 June 1993 in Berkeley, California.

The Workshop and this report were supported in part by the California Public Health Foundation.

Send correspondence to Myrto Petreas, Hazardous Materials Laboratory, Cal EPA, 2151 Berkeley Way, Berkeley, California 94704. Telephone (510) 540-3003. Fax (510) 540-2305.

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Background

A workshop was organized by the Hazardous Materials Laboratory of the Cal EPA on June 13-15, 1993 in Berkeley, California, to consider the effects on the reproductive, endocrine, neurodevelopmental, and immune systems in infants from perinatal exposures to polychlorinated dioxins, dibenzofurans, and biphenyl mixtures. The workshop, co-sponsored by the U.S. EPA, NIEHS, and the California Public Health Foundation, convened an international group of scientists with expertise in pediatrics, chemistry, epidemiology, toxicology, endocrinology, and the reproductive and behavioral sciences to review and discuss current, recently completed, or planned studies of the effects of perinatal exposures to these compounds on the newborn.

The phrase "dioxin-like compounds" (DLCs) used in the workshop title refers to agents that bind to the Ah receptor. These include representatives of the coplanar, halogen-substituted multiring structures such as the polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and some of the coplanar congeners in the polychlorinated biphenyl (PCB) mixtures. The most toxic and well studied of these is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

The objectives of the workshop were: to review the current status of research in the field through presentations by researchers of ongoing, completed or planned studies; to provide a multidisciplinary forum to share insights on the different effects of exposures to DLCs, and to review the use of biomarkers in perinatal studies; and to strengthen future research by establishing contacts and encouraging collaborations between research groups and by setting priorities for future studies.

Organization

The effects of perinatal exposures on the reproductive, endocrine, neurodevelopmental, and immune systems of the offspring were discussed in consecutive sessions, and are summarized in this report. Appendix 1 presents a summary, in chronological order, of all of the studies presented in the workshop sessions, identifying for each the investigator, study design, measures of effect, measures of exposure (compounds under study, source of exposure, matrix/tissue analyzed for dose level), and study conclusions. Fuller descriptions of these studies are given in the accompanying articles, authored by the co-chairs of each session.

In the opening session, speakers gave background information and outlined the task of the workshop. A. Gilman emphasized that organochlorine residues (OCs) continue to persist in the environment. Although the levels of many OCs in western nations have declined over the past decade, populations in different parts of the world show significant deviations from these trends. Increased global use of some persistent OCs, e.g., DDT, toxaphene, PCBs, which are banned or severely restricted in western nations, has led to increased levels of OCs in the Arctic ecosystem. Total global use of DDT may, in fact, be greater in this decade than in the 1970s, when it was banned in North America. U. Ahlborg stated that concern over widespread distribution of these compounds, especially the dioxins, dibenzofurans, and PCB mixtures, and the health consequences of perinatal exposures, have led to the initiation of risk assessments by the World Health Organization.

The next two speakers contrasted exposures of infants and adults. L. Goldman described several factors that place infants at higher risk than adults from exposures to OCs: physiologic factors (lower barriers to absorption through skin, GI tract, and lungs; lower levels of detoxifying enzymes at birth); nutritional factors (breast milk as major source of nutrition; higher caloric intake per body weight); and behavioral factors (closer dermal contact with the outside and household environments; hand-to-mouth exploratory behavior). G. Lindstrom indicated that nursing infants retain almost all of the 2,3,7,8-substituted dioxins and furans that they ingest from breast milk. Nursing infants, on a bodyweight basis, have a dietary intake of TCDD and its equivalents (I-TEQs) that is 100-fold greater than adults; uncorrected for body weight, infant dietary intake is 10-fold higher than adults. Exposure of the fetus is also significant, even though transfer of DLCs from the placenta to the fetus is incomplete (i.e., levels in the mother are higher than levels in the fetus).

W. Rogan and J. Jacobson described their published work which identified developmental (growth retardation and ectodermal abnormalities) and neurobehavioral (cognitive and motor functions) deficits in children whose mothers consumed PCB-contaminated cooking oil or large amounts of OC-contaminated fish during pregnancy (14-15,17-19,23,24). The possibility that these exposures cause delayed or long-term effects, as suggested by animal studies, has prompted follow-up, second-generation reproduction studies of exposed cohorts in Seveso, Italy and in Taiwan by P. Mocarelli and W. Rogan, respectively.

Conclusions and Future Directions

Overall conclusions from the workshop, as well as recommendations for future research, are listed below. Following these, conclusions and research needs are given for each study area covered by a workshop session (reproductive, endocrine, neurodevelopmental, and immune toxicity).

General

Conclusions

The current dominant paradigm is that the biological activities of TCDD and the DLCs arise from their binding to the Ah receptor, and the biological effects that occur are believed to be Ah receptor-mediated.

Some components of PCB mixtures (DLCs) bind tightly to the Ah receptor and are believed to operate via Ah receptor-dependent mechanism(s). Other components do not, and must act through mechanisms that are independent of the Ah receptor (including phenobarbital-type induction of drug-metabolizing enzymes, binding to other (e.g., estrogen or thyroid hormone) receptors, or altering biogenic amine concentrations). Other PCB components may act via both Ah receptor-dependent and receptor-independent mechanisms.

There is a similarity in response in animals and humans to TCDD and DLCs. For every end point examined, human response is replicated in some species of laboratory animal: growth retardation (monkeys, rats), ectodermal effects (monkeys), spatial learning/memory deficits (monkeys, rats), and changes in lymphocyte subpopulations (monkeys). For well-studied human end points such as chloracne and enzyme induction, homology exists with several animal species.

A working hypothesis for the mechanism of action of TCDD and DLCs is that they act as endocrine disrupters or "environmental hormones" in perinatal systems. In this way, they provide inter- or intra-cellular signals that alter growth, differentiation and function of cells in a tissue-, stage-, or cell-specific manner.

Consistent with this hypothesis, TCDD and DLCs have been demonstrated to act as multisystem effectors, affecting the developing immune, neurobehavioral, endocrine, and reproductive systems. Acting as hormones or endocrine disruptors, they may cause neoplasia by altering patterns of differentiation/proliferation of specific tissues in the developing or adult organism.

Research Needs

More interaction is needed among laboratory researchers, epidemiologists, and biostatisticians. Collaboration between laboratory researchers and epidemiologists enables animal data to generate hypotheses for human studies, and vice versa. Human and animal studies need biostatistical support so that data are useful for hazard identification, risk assessment, and public health intervention.

Summaries are needed of human and animal studies (male and female) of each organ system. These summaries would describe exposure or dose levels, nature of effects, strength of evidence, and confidence in the studies.

Better data are required for exposure assessment.

The prenatal period is a sensitive period (see animal and human studies) and needs further study.

Research is needed in human populations to investigate the potential for delayed effects in the reproductive, neurobehavioral, and neuroendocrine systems, especially among postpubescent cohorts exposed perinatally.

Reproductive Effects

Conclusions

PCB mixtures cause different reproductive effects than DLCs. Lactational exposures to PCB mixtures (Aroclor 1254) cause infertility in male rat offspring without affecting their sperm count (37). TCDD decreases sperm count but does not affect fertility (4-5). Components of PCB mixtures may act like phenobarbital-type inducers, estrogens, or effectors of thyroid status or dopamine levels, while DLCs presumably operate through the Ah receptor-mediated events.

TCDD reduced fertility in female monkeys (1) and may exacerbate endometriosis (38). In utero and lactational exposures to TCDD caused changes in sexual differentiation in rat pups: feminization of males (reduced anogenital distance, sperm count, and accessory sex glands; abnormal mounting behavior) and urogenital abnormalities in females (absent vaginal openings, cleft clitoris) (2,4,5).

PCB congeners produced growth retardation in offspring of dosed female rats (3); chronic PCB exposures in female monkeys produced growth retardation in offspring (1); and infants born to mothers exposed to PCB/PCDF-contaminated rice oil or contaminated fish had low birth weights (14-23).

Birth size among male infants (Inuits) was inversely related to PCB concentration in breast milk of the mother (7,29).

Research Needs

The effects of perinatal exposures to TCDD and DLCs on the reproductive system of adult males are reasonably well-described; information is needed on mechanisms (e.g., effects on spermatogenesis and sexual differentiation).

Research is needed on the effects of these compounds on nonpregnant females (e.g., age at menarche, cyclicity, time to conception, and endometriosis).

Animal studies indicate delayed effects of perinatal exposures on reproductive systems. Perinatally exposed cohorts need to be followed beyond puberty and examined for delayed effects such as age at onset of puberty, age at menarche, reduced fertility, abnormal cyclicity, decreased sperm count, and premature menopause.

Endocrine Effects

Conclusions

Exposures of pregnant female rats to small amounts of TCDD caused changes in indices of androgenic status in male offspring: spermatogenesis was inhibited; sexual behavior and the pattern of LH secretion was less masculine and more feminine (2,4,5).

Prenatal exposures to specific PCBs (#118, #153) reduced brain levels of T4 in offspring of exposed female rats (3).

Other specific PCB congeners (#77, #47) caused age-dependent changes in biogenic amine neurotransmitter levels in rats: in adults dopamine levels were reduced by ortho, but not coplanar, PCBs; dopamine levels were raised by perinatal exposures to either (9,12).

TCDD reduced responsiveness of ventral prostate to testosterone in male offspring of dosed female rats without affecting responsiveness of seminal vesicles (4).

TCDD also inhibited sexual differentiation in the CNS without altering sexual dimorphisms in estrogen-receptor concentrations or volumes of brain nuclei (5).

Research Needs

The mechanistic relationships between DLCs, T4 and the neurodevelopmental system need further study.

Studies should focus on measurements of T4, TSH, and TRH, especially at different levels in the neuroendocrine axis.

Levels of both free and bound T3 should be examined.

More studies on binding of PCBs, metabolites, and DLC congeners to TBG and TTR are needed. Binding to TTR in rodents is important; the significance of the small amount of DLC-binding to TTR in humans should be explored.

Estrogen, testosterone, and corticosteroid levels should be measured in younger cohorts.

Neurobehavioral Effects

Conclusions

Neurobehavioral effects (spatial learning/ memory and motor deficits) may arise from complex interactions between neuroendocrine and neurophysiological systems (e.g., specific PCB congeners decrease levels of dopamine in prefrontal cortex of adults, as well as decrease brain levels of T4 in offspring of dosed female rats, possibly affecting neuronal branching) (3,8-13).

Perinatal exposures of monkeys to PCB mixtures, and of rats to specific PCB congeners produced spatial learning/memory deficits (10-13). Cognitive functioning was impaired among children exposed in utero to mixtures of OCs, including PCBs (14,15). PCBs produced motor deficits that persisted to age 2 among children exposed in utero (17-21,23).

Research Needs

Studies employing specific PCB congeners are needed to investigate the associations between perinatal DLC exposures, spatial learning/memory deficits, and levels of dopamine and T4 in specific regions of the brain.

Test batteries for neurobehavioral effects should include standardized, narrow-band, and challenge or stress tests.

Studies of neurobehavioral effects of chemicals are difficult because known environmental factors can overwhelm any effect of the chemical. In rats, sexual differentiation of the CNS is affected by perinatal exposures to TCDD (2,4,5). In humans, our ability to examine this association between DLCs and sexual differentiation awaits the development of measures which are less affected by confounding social/ "environmental" factors.

Reliable measures of disease end point are required (e.g., health care providers in clinic networks should be trained to rate neurobehavioral deficits by consistent criteria).

Immunologic Effects

Conclusions

A working hypothesis is that perinatal exposures to DLCs and PCBs alter the pattern of differentiation of cells of the immune system and, as a consequence, change the responses of immune cells. The extent and magnitude of these changes depend upon when in the development of these cells the exposures occur: exposures early in development will affect the primordial stem cells, while later exposures affect cells in a more developed system.

The thymic atrophy caused by TCDD may arise in part from the depletion by TCDD of prolymphocytes in the bone marrow. TCDD-induced thymic atrophy is accompanied by decreases in lymphocyte stem cell markers which are present only in bone marrow prothymocytes (terminal deoxynucleotidyl transferase (TdT) and recombinase activating gene (RAG) (27,28). In irradiated mice, TCDD-treated prothymocytes are unable to repopulate the thymus.

DLCs may affect the primary antibody response: in humans (Inuits--PCBs and dioxins) (29) and rodents (mice-- TCDD) (27,28,34,35) prenatal exposure decreases the ratio of T helper to T suppressor cells in the thymus.

TCDD may have immuno-suppressive or immuno-enhancing effects in rodent species (26). Perinatal exposures to animals affect mainly T cell responses (27,28).

Perinatal exposures to PCBs affect primary antibody response, as suggested by a 20-fold higher incidence of infectious diseases (e.g. meningitis, measles) and ear infections (otitis media among 1-year-old Inuits with high PCB exposures) than among lesser exposed controls (7,29); by a low immunization take rate among Inuits compared to controls (7,29); and by changes in ratios of lymphocyte sub-populations in animals and humans (7,26-30, 34,35).

Research Needs

Biomarkers of immunotoxicity continue to be developed; the effect of TCDD and PCBs on lymphocyte subset ratios (e.g., CD4/CD8) is still unclear in animals and humans.

Studies are needed on the primary antibody response in children with high PCB exposures, possibly employing vaccine challenge tests.

References

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2. Gray LE, Ostby JS, Kelce W, Marshall R, Diliberto JJ, Birnbaum LS. Perinatal TCDD Exposure Alters Sex Differentiation in Both Female and Male LE Hooded Rats. Dioxin '93 Conference, Vienna, Austria, 1993.

3. Ness DK, Schantz SL, Hansen LG, Mostaghian J. Effects of perinatal exposure to specific PCB congeners on thyroid hormone concentrations and thyroid histology in the rat. Toxicol Lett 68:311-323 (1993).

4. Bjerke DL, Sommer RJ, Moore RW, Peterson RE. Effects of in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on responsiveness of the male rat reproductive system to testosterone stimulation in adulthood. Toxicol Appl Pharmacol 127:250-257 (1994).

5. Bjerke DL, Brown TJ, MacLusky NJ, Hochberg RB, Peterson RE. In utero and lactational exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin feminizes and demasculinizes sexual behavior without altering volumes or estrogen receptor capacities of sexually dimorphic brain nuclei. Toxicol Appl Pharmacol 127:258-267 (1994).

6. Koopman-Esseboom C, Huisman M, Weisglas-Kuperus N, van der Paauw CG, Tuinstra LG, Morse DC, Brouwer A, Sauer PJJ. Effects of PCBs and dioxins during pregnancy and breast feeding on growth and development of newborn infants. A study design and preliminary results. Proceedings of the 12th International Dioxin Conference, Tampere, Finland, 1992.

7. Dewailly E, Bruneau S, Ayotte P, Laliberte C, Gingras S, Belanger D, Ferron L. Health status at birth of Inuit newborn prenatally exposed to organochlorines. Chemosphere 27:359-366 (1993).

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9. Seegal RF. The neurochemical effects of PCB exposure are age-dependent. Arch of Toxicol Suppl 16:128-137 (1994).

10. Levin ED, Schantz SL, Bowman RE. Delayed spatial alternation deficits resulting from perinatal PCB exposure of monkeys. Arch of Toxicol 62:267-273 (1988).

11. Levin ED, Schantz SL, Bowman RE. The lesion model of neurotoxic effects on cognitive function in monkeys. Neurotoxicol Teratol 14:131-141 (1992).

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14. Jacobson JL, Jacobson SW, Humphrey HEB. Effects of in utero exposure to polychlorinated biphenyls and related contaminants on cognitive functioning in young children. J Pediatr 116:38-45 (1990).

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Appendix 1. Studies on perinatal exposure to dioxin-like compounds presented at workshop.

Study, presenter	Study design	Effect measures	Compound(s)	Exposure	Matrix/dose	Conclusions	References
Reproduction  Ayotte P	Measures of effect following in utero exposure of Inuits to PCBs and related contaminants	P450 induction, Ah receptor, stress protein, T-cell sub- sets, natural killer cell assay, primary antibody response, SCE, birth weight	PCBs (congener specific), organochlorine compounds, PCDD/PCDFs	Transplacental: maternal ingestion of fish and sea mammals	Placenta, cord blood	Study starting in 93/94
Reproduction  Buck G	Prospective cohort of 11,717 anglers and 6,579 wives/partners. Exposure vs reproductive/ developmental end points and selected chronic diseases	Standardized fertility rates; fetal growth and birth size;subclinical health effects	68 PCBs, PCDD, PCDF, DDT, DDE, Hg, Pb, mirex, and hexa chlorobenzene	Transplacental: ingestion of sports fish (paternal, maternal consumption)	Lifetime and pregnancy-specific consumption, serum profiles, breast milk levels.	Study in progress
Reproduction  Cicmanec J	Reproductive study of rhesus monkeys exposed to Aroclor 1254	Body weight, hematology, serum, urinalysis, semen, fertility, clinical changes	Aroclor 1254	Transplacental	0, 5, 25, 100 µg/kg, 14 months	Chronic exposure of female rhesus monkeys to PCBs at 100 µg/kg produced lower fertility and abnormal finger and toe nails; 25 µg/kg resulted in decreased bw and growth of offspring	(1)
Reproduction  Gray LE	Perinatal TCDD exposure of female and male LE hooded rats	Sex differentiation, urogenital malformations, sperm count, mating behavior	TCDD	Transplacental: lactational	1µg /kg on GD 8 and GD 15	Perinatal exposure to TCDD affected sexual differentiation in male and female offspring of dosed female rats: males had reduced sperm count and changes in sex accessory glands; females had urogenital abnormalities	(2)
Endocrine  Schantz SL	Thyroid hormones and brain development in Sprague-Dawley rats exposed to PCBs	Weights of liver, brain and thyroid; total serum T3, T4; histological evaluation of thyroid; reproductive and developmental parameters	PCBs # 28, 118, 153	In utero and lactational exposure	Dosing of dams with PCBs: # mg/kg/day 28 8 or 32 118 4 or 16 153 16 or 64	Perinatal exposure to two PCB congeners (118 and 153) produced lower T4 concentrations and growth retardation in offspring of dosed female rats	(3)
Endocrine  Moore R	In utero and lactational TCDD exposure in rats. Effects on:responsiveness to androgens in adulthood; sexual differentiation of CNS; spermatogenesis	Sex organ weight;DNA, protein, testosterone, 5a-di-hydrotestosterone; sexually dimorphic nuclei: volumes and estrogen receptor distributions; Sertoli cell division; testis DNA ploidy	TCDD	In utero and lactational exposure in rats	Single oral maternal dose: 0.7µg/kg on GD 15	Perinatal exposure to TCDD reduced responsiveness of ventral prostate to testosterone in male offspring of dosed female rats, with no effect on the responsiveness of seminal vesicles. TCDD did not affect sexual dimorphism in brain morphology	(4,5)
Endocrine  Koopman-  Essebom C	Prenatal, postnatal effects of PCBs and dioxins on human infants	Growth, neurological, psychomotor development; thyroid hormonemetabolism (TT4, TT3, FT4, TSH)	PCDDs, PCDFs PCBs (#118, 138, 153, 180) PCDDs, PCDFs, coplanar PCBs	In utero Lactational	Maternal plasma,umbilical cord plasma Breast milk	Study in progress	(6)
Endocrine  Dewailly E	Effects of prenatal exposure to PCBs, PCDDs and PCDFs on TSH in the Inuit population	TSH and clinical parameters: weight,height, cranial and thoracic circumference	PCBs (# 28, 52, 10, 118, 138, 153, 170, 180, 183, 187) & eight chlorin. pesticides	In utero	In utero exposure assessed by breast milk levels	For male infants, birth size inversely related to PCB concentrations in breast milk of the mother	(7)
Neurobehavior  Seegal R	Comparison of effects of Aroclor 1016 and 1260 on nonhuman primates Perinatal exposure of rats	Alteration in brain biogenic amine concentrations (decreases esp. in DA concentrations);alterations in brain biogenic amines;increases of biogenic amine concentrations	Aroclor 1016 and 1260 Aroclor 1016 PCBs (# 77, 47)	Adult exposure for 20 weeks (0.8­3.2 mg/kg/day) Perinatal exposure of rats from GD6 through weaning	Brain tissue (caudate, hypothalamus, substantia nigra putamen); Brain tissue (see above)	PCBs cause age-dependent neurochemical changes: in adults, o-substituted, but not coplanar, PCBs reduce neurotransmitter (dopamine) levels; in newborns, perinatal exposure to o-substituted or coplanar PCBs elevate dopamine levels	(8,9)
Neurobehavior  Schantz SL	Effects of PCB congeners and mixtures on cognitive functioning in rats and monkeys	Cognitive functioning Delayed spatial alternation task	Aroclor 1248 PCBs (# 28, 118 & 153)	In utero and lactational	Chronic exposure (monkeys) GD 10­16 (rats)	Perinatal exposure of monkeys (chronic; PCB mixtures) and rats (GD 10­16; PCB 28, 118 (mono-o),53 (di-o) produced spatial learning/memory deficits, suggesting changes in prefrontal cortex	(10­13)
Neurobehavior  Jacobson J	Effects of in utero exposure to PCBs.and related contaminants on physical growth, cognitive functioning in children	Cognitive functioning, physical growth	Aroclor 1260	Transplacental; lactational	Umbilical cord serum, breast milk	Short term memory/attention and physical growth impaired among children with in utero exposure to PCBs.	(14,15)
Neurobehavior  Rogan W	Perinatal PCB exposure and child development in N.Carolina (n=930) Effects of prenatal exposure to heat-degraded PCBs in Taiwan (Yu-Cheng)	Morbidity, developmental delay (Brazelton, Bayley, McCarthy Scales) Ectodermal disorders; physical, neurodevelopmental delays	PCBs, DDE PCBs, PCDFs (degraded PCB oil)	Transplacental; lactational Transplacental	Cord blood, breast milk, formula	In North Carolina, prenatal exposure to PCBs produced motor deficits among childran: at birth, the more highly exposed were hypotonic and hyporeflexic. In Taiwan, prenatal exposures to degraded PCB oil caused growth retardation, cognitive deficits and ectodermal abnormalities, including excess pigmentation, deformed nails, and hirsuitism.	(16­24)
Neurobehavior  Smoger G	Quantitative EEG and lymphocyte phenotype assessment after exposure to dioxin in Times Beach	Frontal lobe abnormalities in elect. conductivity, CD4/CD29 and & light chain de-pression, attention/conc. deficits, incr.rates of respiratory infections	TCDD	Transplacental House dust	TCDD levels of 0.02 to 2.2 ppb measured in house dust 10 years post exposure	At incompletely assessed exposure levels, frontal lobe abnormalities in EEG activity as compared to EEG measurements of historical controls. Suggestive of effects on attention/concentration and rates of respiratory infections.
Neurobehavior  Weisglas-  Kuperus N	Neonatal PCB exposure and neurodevelopmental deficits; cohort study	Immunologic status, thyroid status, neurodevelopment	PCBs (# 138, 153, 180); Pb, Cd, Hg, Al	Transplacental; lactational	Cord blood, breast milk	Study to start in September, 1993
Neurobehavior  Muckle G	Study of 0 to 2-year-old children exposed to PCBs and heavy metals in utero	Birth status; physical growth; health status; psychomotor, mental abilities; information processing, neurobehavior	PCBs (total); PCDDs /PCDFs; Hg, Pb	Transplacental Arctic food chain	Maternal serum: Aroclor 1260 x=15.14 µg/L md=11.0 SD=12.0 range=1.6­65.0	Study in planning phase
Neurobehavior  Needham L	Neurobehavioral study of in utero exposure and effects associated with seafood consumption in the Faeroe Islands	Neurodevelopment	PCBs, Hg, Pb, Se	Transplacental North Atlantic food chain	Maternal hair, cord tissue, cord blood	Ongoing study	(25)
Immunotoxicity  Smialowicz R	Effects of 2,3,7,8-TCDD on humoral immunity and lymphocyte sub-populations in mice and rats	Antibody plaque-forming cell (PFC) response to immunization with sheep erythrocytes and splenic lymphocytes; subpopul.analysis	TCDD	Adult exposure	Single ip injection of rats or mice at doses ranging from 0.1­30 µg/kg	Species differences were found among adult rodents in the immunotoxic effects of single injections of TCDD (0.1­30 µg/kg): mice were more sensitive, and immunosuppressed; rats were immuno-enhanced, with decreased T suppressor cells (CD4­CD8+), as occurs in a primary antibody response	(26)
Immunotoxicity  Gasiewicz T	Effects of TCDD on the thymus of mice	Developing T-cells and B-cells, by stem cell markers (TdT and RAG)	TCDD	In utero	Single exposure to dam: 1­30 µg/kg on GD 14­18	In mice, fetal thymus more sensitive than adult. Thymic atrophy may result from direct effect of TCDD on bone marrow cells, i.e., TCDD decreases lymphocyte stem cell populations (prothymocytes) and the induced thymic atrophy may result from the inability of prothymocytes to repopulate the thymus.	(27,28)
Immunotoxicity  Dewailly E	Immune effects in Inuit infants	Humoral and cellular immunity; infectious diseases	PCDD, PCDF, coplanar PCBs, chlor pesticides	In utero; lactational	Breast milk	Higher incidences of infectious diseases (e.g., meningitis, measles, and otitis) in 1-year old Inuits than in control population of southern Quebec. Among Inuit infants whose levels of exposure to PCBs, PCDDs, and PCDFs are elevated, some dysfunctional primary immune responses were observed.	(29)
Immunotoxicity  Helge H	Effect of TCDD on lymphocyte subsets and P450IA dependent enzyme activity in monkeys, human infants and children	Lymphocyte subsets by FacScan; breath test (13C-caffeine-methacetine) for P450IA activity	TCDD PCDDs, PCDFs	Monkey (s.c. injection) Infant (breast milk)	Monkeys: 10 ng/kg Infants: breast milk 1.7­7.8 ng/kg fat	Dose-dependent, reversible changes in ratios of lymphocyte subpopulations (especially loss of CD4+CDw29+) and induction of P4501A1/P4501A2 in marmosets at doses of 10 ng/kg and below; no difference in lymphocyte ratios from breastfed and formula-fed infants.	(30­35)
Biomarkers  Clark G	Biochemical responses in exposed human populations	Ah receptor levels, Cyp1A1, TNF, clinical end points, health surveys	TCDD	Adult occupational and accidental exposure	Chronic exposure (Boehringer) Acute exposure (Seveso)	Ongoing studies of populations (Seveso and Boehringer cohorts) with exposures to TCDD in which levels of Ah receptor, CYP1A1, TNF and IL-1B genes are measured.	(36)

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Last Update: October 7, 1998