e.hormone | hormones and the environment

e.hormone 2004 Conference Summaries

The conference summaries express the authors' views of the meeting events. They do not necessarily represent the views of e.hormone.tulane.edu or its advisory board

E.HORMONE 2004: THE CUTTING EDGE OF
ENDOCRINE DISRUPTOR RESEARCH (October 27-30, 2004)

e.hormone 2004: The Cutting Edge of Endocrine Disruptor Research was sponsored by the Center for Bioenvironmental Research of Tulane and Xavier Universities and was held in New Orleans, Louisiana, October 27-30, 2004.

Session summaries (Posted: January 5, 2005)

Environmental Signals and Sensors
Endocrine Disruption: Gene-Environment Interaction
Estrogens and Development Workshop: Translation of Field, Laboratory, and Clinical Findings into Human Health Outcomes
Endocrine Disruptors: Epidemiologic Approaches (presented by the US Environmental Protection Agency)

Authors

Wendy L. Hessler, e.hormone Content Manager, New Orleans, Louisiana
Robert Wallace, CBR Tulane and Xavier Universities, New Orleans, Louisiana

Environmental Signaling Network Fellows (National Science Foundation)

Deanna Scher, University of Minnesota, Minneapolis
Marlo K. Sellin, University of Nebraska, Omaha
Elizabeth A. Stokes, Georgia State University, Atlanta
Monica E. Unseld, University of Louisville, Kentucky
Stacy N. White, University of Texas Southwestern Medical Center, Dallas
Gwendolyn Wood, The Rockefeller University, New York

Session 1. Environmental Signals and Sensors

• Estrogen receptor beta (ER beta), discovered almost a decade ago, is now less of a mystery and more of a hopeful possibility, according to Jan-Åke Gustafsson, Karolinska Institutet, Sweden. ER beta is found in cells of several mammalian tissues, including human prostate and testis. Although chemically similar to ER alpha, the receptors have opposite effects. Alpha promotes tissue growth, or proliferation, while beta inhibits the process. New drugs targeting ER beta are being developed to treat autoimmune diseases, such as Crohn's disease and arthritis, and prevent/treat cancers such as leukemia and prostate cancer. Some believe these may be more effective than current prostate cancer treatments that unintentionally block ER beta's actions. Prostate cancer research continues to show that overexposure to estrogen early in development alters key cell development patterns (epithelial differentiation) that predispose aging mice to the disease. A delicate balance and interplay between ER alpha and beta self-regulates this process setting the stage for healthy prostate growth, suggests new research. In recent mice experiments, ER alpha governed prostate tissue expansion during the first 2 to 3 weeks until ER beta kicked in and suppressed growth suggesting estrogen imprinting, stroma tissue alterations, and estrogen receptor interplay are all important to a healthy prostate. (Wendy L. Hessler)

• Many environmental contaminants are suspected or known neurotoxicants. Developmental neurotoxicity (DNT) is of particular concern due to the vulnerability of the brain during periods of development. Although EPA has recently implemented a standard DNT battery to identify developmental neurotoxins and their effects, this battery is ineffective for several reasons, said Theodore Slotkin, Duke University Medical Center, North Carolina. For example, the DNT battery is based on detectible morphological endpoints and standard behavioral endpoints that do not account for the variety of potential outcomes. The battery does not examine every important period of development, and sex-related differences are not specifically addressed. Overall, the battery is costly and inadequate due to the potential for false negatives. Chlorpyrifos is an example of how the assumptions in the DNT battery are ineffectual. The neurobehavioral effects of chlorpyrifos are sex-selective and the emergence of behavioral deficits is seen only with the onset of puberty, after a prolonged period of normal development. To improve the effectiveness of DNT studies, high-throughput in vitro and non-mammalian screens and arrays should first be conducted to identify which outcomes to look for in subsequent mammalian models. (Deanna Scher)

• Combining molecular genetic information from online databases and other sources with a novel computer software program called PAGen@UIC can effectively pinpoint which genes estrogen regulates. Human and mouse online databases provide information about transcription factors, binding sites, and more that can be used to predict estrogen's influence on genes, said Sitharthan Kamalakaran, Cold Spring Harbor Labs, New York. Kamalakaran recounted recent efforts to streamline the computer-based process, confirm its accuracy, and explore the feasibility of widespread use of the new method. Using the tool, Kamalakaran and collaborators successfully predicted and confirmed that estrogen can regulate the NRIPI gene in MCF 7 breast cancer cells and the breast cancer resistance protein gene (BCRP) in ER-alpha expressing cells. The software will be publicly available soon. (Wendy L. Hessler)

• It is well known that female snails, abalone, and other mollusks can develop male sex parts - known as imposex - after exposure to the endocrine disruptors tributyltin and triphenyltin (organotin compounds found in marine antifouling paints). Research from Japan finds that the retinoid X receptor (RXR) plays an important role in the development of imposex, which affects about 150 species worldwide, according to Toshihiro Horiguchi, National Institute for Environmental Studies, Japan. Populations of several important mollusk species in Japan, including the intertidal rock shell, the ivory shell, and the abalone, have plummeted or gone extinct in part because of sterilization and other reproductive problems associated with imposex conditions (such as penis and vas deferens in females and sperm development in ovaries) triggered by organotins. While testing RXR's role in imposex, researchers found tributyltin and triphenyltin strongly bind the human RXR, female rock shells develop imposex after being injected with RXR's natural ligand 9-cis retinoic acid, and 9-cis retinoic acid and organotins bind to the rock shells RXR equivalent receptor. All this suggests RXR facilitates male genital tract development in female mollusks. (Wendy L. Hessler)

Session 2. Endocrine Disruption: Gene-Environment Interaction

• Jimmy L. Spearow, University of California at Davis, discussed some of the issues surrounding the choice of animal models and their potential implications on data regarding environmental signaling. Relevant published literature and Spearow's original data suggest that rodent strains differ in their susceptibility to endocrine disruption. Several issues should be considered when evaluating how vulnerable a population or species might be to toxic chemical exposure, Spearow said. Important issues include: 1) the genetic variability of outbred strains can mask detection of the effects of toxicants on genetic variability and using multiple isogenic inbred strains (F1s) from diverse genetic backgrounds is suggested; 2) many outbred lines/strains obtained from laboratory suppliers were selected for high prolificacy, large litter size, and resistance to toxins, which can often impact the outcome of studies on toxicants; and 3) the potential for mechanistic interactions between genetic susceptibility to estrogenic agents should be considered in the design of endocrine disruptor screening assays. These concerns were outlined in a Reviewer's Appendix and submitted to the US Environmental Protection Agency in response to the "Species/Stock/Strain in Endocrine Disruptor Assays" white paper. The appendix has yet to be released, said Spearow. For more details, contact Dr. Spearow at jlspearow@ucdavis.esu. (Gwendolyn Wood)

• Dietary estrogens can be an influential factor when studying endocrine disrupting compounds, said Julius Thigpen, National Institute of Environmental Health Sciences, North Carolina. Many kinds of animal feed used in laboratory studies are high in phytoestrogens. Because these compounds chemically resemble the natural estrogen estradiol and the synthetic estrogen diethylstilbestrol, they can bind with estrogen receptors and may confound studies of endocrine disrupting compounds. The potencies and brand variation between two common dietary estrogens, daidzien and genistein, were reviewed to illustrate the wide differences in feed content. Dr. Thigpen also included a checklist of important factors to consider when selecting diets for animals involved with endocrine disruptor research and recommends that when selecting a diet, a low-estrogen feed should be chosen in order to minimize any variables that could impact endocrine-sensitive endpoints. (Elizabeth A. Stokes)

• Epigenetics can be described as a heritable change in gene expression that is not accompanied by a change in DNA sequence. Specifically, methylation of normally unmethylated CpG islands has been observed in various cancers. Kenneth Nephew, Indiana University School of Medicine, discussed how the epigenetic event of hypermethylation of CpG islands results in silencing of estrogen receptor signaling and may play a major causal role in cancer by silencing key estrogen receptor target genes. When estrogen receptor signaling was silenced using small interfering RNAs (siRNA), expression of the progesterone receptor (PR), an estrogen receptor target gene, was decreased in estrogen sensitive breast cancer cell lines. Additionally, siRNA-induced estrogen receptor silencing resulted in a decrease in protein complexes normally associated with transcriptionally active chromatin of PR. Conversely, protein complexes associated with transcriptionally inactive chromatin were subsequently increased at the CpG islands of the PR promoter. Methylation was detected at CpG sites adjacent to the complex and gradually extended across the PR promoter, but changes in CpG island methylation followed chromatin changes. This acquired DNA methylation may set up a permanent mark to establish a heterochromatin state for subsequent long-term gene silencing. Finally, microarray analysis demonstrated that silencing of estrogen receptor signaling resulted in methylation of several estrogen receptor target genes in addition to the PR. These findings provide insight into how epigenetic events such as hypermethlyation of CpG islands may influence the development of many cancers. As estrogen signaling regulates many gene loci, a disruption in this pathway may initiate epigenetic memory in multiple downstream targets of ER alpha and may, in part, contribute to the resistance of hormonal therapies in some ER alpha-positive patients. (Stacy N. White)

• Leydig cells are specialized cells in the testes that make male hormones. Rodent Leydig cells have both androgen receptor and the estrogen receptor (ER) alpha. Experimental mice lacking ER alpha have reduced blood levels of luteinizing hormone (LH). LH controls spermatogenesis and testosterone (T) production and triggers more active steroidogenic activity that transforms T into other steroids, decreasing androgen blood levels, explained Benson Akingbemi, Population Council, New York. Estrogen, then, is very important in regulating male reproduction. Certain phthalates can interfere with the LH/hormone balance. For instance, MEHP, a metabolite of the common phthalate DEHP found in plastics, reduces production of LH and T in Leydig cell cultures. However, mice exposed directly to DEHP from both 21-48 days after birth and 21-90 days after birth produced elevated levels of both LH and T. In normal animals, a negative feedback loop exists between LH and T so simultaneous higher levels of both chemicals is odd. Testes tissue studies indicated that DEHP stimulated mitosis so the animals were producing more Leydig cells. How had this happened? Apparently, the increased rate of T synthesis coupled with the increased activity of the aromatase enzyme, which transforms T into estradiol, led to higher estrogen levels. Estrogen, in turn, stimulates Leydig cell proliferation. This effect decreased over time, so it may be reversible. Implications for human health are many. Higher than normal androgen levels have been correlated with male precocious puberty. Indeed, precocious reproductive development was observed in the DEHP treated male rats. (Robert Wallace)

Session 3. Estrogens and Development Workshop: Translation of Field, Laboratory, and Clinical Findings into Human Health Outcomes

• John A. McLachlan, Tulane University, Louisiana, introduced the hypothesis of a developmental estrogenization syndrome. The syndrome may be the result of exposure to endogenous, pharmaceutical, or environmental estrogens. Subsequent speakers presented more information to stimulate discussion: Jeff Boyd discussed a molecular basis for developmental estrogenization syndrome; Taisen Iguchi addressed the effects of estrogens in development of laboratory animals; and Ann Cheek presented information about the impact of environmental estrogens and developmental effects in wildlife. Participants discussed the translation of field, laboratory, and clinical findings into human outcomes. The exchange of knowledge and ideas in this workshop will serve to further delineate the manifestation and existence of the syndrome. (Stacy N. White)

• Jeff Boyd, Memorial Sloan-Kettering Cancer Center, New York, examined the role of estrogen in type I and II endometrial carcinoma. Microsatellite detection found instability in the genetic code in the DNA mismatch repair system. Estrogen induced mutations to three genes that comprise a part of the repair system result in loss of function and increased cancer risk. Endogenous estrogen and environmental estrogens, such as diethylstilbestrol and the drug tamoxifen, result in hypermethylation of the genes and inactivation, or silencing, of the tumor repressor genes. (Monica E. Unseld)

• Taisen Iguchi, Center for Bioenvironmental Research, Japan, suggests that we need a new model for endocrine disrupter toxicity focusing on receptor-mediated toxicity. In other words, if there is no receptor, there is no toxicity. The receptor, under the influence of these exogenous chemicals, makes the wrong chemical or makes the right chemical in the wrong place or at the wrong time. This type of toxicity differs from regular toxicity by its persistent (organizational) effects. For example, female rats exposed perinatally to estrogen still respond to estrogen stimulation in the absence of ovaries and females with testes implanted at a young age exhibit a persistent estrus. This indicates that there are critical developmental periods and that changes at these times will have permanent consequences. This is especially important because estrogen has wide developmental effects that go beyond just the reproductive system. Testosterone also has broad effects, but di-hydroxy-testosterone has less general effects. The synthetic estrogen diethylstilbestrol (DES) has such large effects because it changes the expression of the Hox and Wnt genes that are largely responsible for development in animals. The effects of DES on the female reproductive tract persist even when the ovaries have been removed, suggesting that it permanently turns on genes controlled by the estrogen receptor alpha system. Bisphenol-A (BPA), a plastic softener that has been shown to cross the placenta in monkeys in only 30 minutes, induces earlier vaginal opening and delays anovulation in rats but has no effect on fertility. BPA has a metabolite (MBP) that is more estrogenic. BPA and nonylphenol affect different genes than estrogen, and the effects differ by tissue. Due to time constraints, other data, including the use of microarrays in wildlife, was not presented. (Robert Wallace)

• Permanent (developmental exposure) or reversible (adult exposure) changes in sex characteristics, biochemical makeup, behavior, and fertility can occur in wildlife exposed to endocrine disrupting chemicals (EDCs), explained Ann O. Cheek, University of Texas School of Public Health. Animals can be feminized or demasculanized, and new research following three generations suggests the demasculanizing effects are more troublesome as they can linger and possibly alter populations. Documented effects in fish (roach, longear sunfish), reptiles (alligators, caimans, and turtles), and amphibians (frogs, newt) dramatize the range of sexual, hormonal, and fertility alterations being found and the breadth of how these are occurring through estrogenic, androgenic, or other hormonal influences or imbalances. Because of the variety of symptoms/responses and population changes over time, it has been difficult to find a reliable marker to measure exposure. Increasing use of comparative biology - such as gonadal sex measurements (for example the distance between anus and genital openings) in vertebrates - could be an effective way to spot male/female-related individual effects and identify similar problems among species. (Wendy L. Hessler)

• Humans are exposed to a variety of estrogens including phytoestrogens, steroidal estrogens, and xenoestrogens. Exposures can occur via skin contact, inhalation, ingestion, or transplacentally, said Gloria Richard-Davis, Ochsner Clinic Foundation, Louisiana. Several factors determine the outcome of estrogen exposures including the route of exposure, exposure dose, timing, and duration. There is a link between reductions in human reproductive health and endocrine-disrupting compounds (EDCs). For example, exposures to diethylstilbestrol (DES) are known to cause reproductive cancers, infertility, pregnancy loss, and fibroids in humans. While DES serves as a prototype for estrogenic exposures, the effects of other EDCs on human reproductive health have yet to be determined. Those doing clinical studies face many challenges especially when trying to determine the causal relationship between exposure and effect. Furthermore, it is nearly impossible to define individual risk and prevention. These challenges present a clear need for collaboration between basic and clinical scientists. (Marlo K. Sellin)

• Although there are an equal number of diethylstilbestrol (DES)-exposed sons as daughters, there are fewer primary studies of the effects of DES on male children, according to Scott P. Kerlin, DES Sons International Network, Ontario, Canada. The DES Sons International Network was organized in 1999 in part to encourage more research on DES sons' adverse health effects. Preliminary data from 1999-2004 are available on 500 members of the Network with confirmed or suspected DES exposure. Health concerns within this group fall into three main categories: 1) endocrine effects (e.g., hypogonadism), 2) affective disorders (e.g., depression), and 3) gender identity/sexually issues. The third health concern is the most surprising, as one-quarter to one-third of the members self-identify as transsexual, transgender, or intersex. Expanded research is planned to increase the size of the cohort and to focus specifically on gender and sexual health issues. (Deanna Scher)

• The rate of testicular cancer varies significantly in developed countries, said Niels Skakkebaek, University of Copenhagen, Denmark. For example, it is higher in Denmark (9 percent) than in Finland, and it is also relatively high among non-hispanic whites from the United States. Other studies show declining fertility and increased frequencies of hypospadias in developed nations. The rate of cryptorchidism (undescended testis), which predisposes to both low fertility and high cancer risk, follows a similar pattern. Low birth weight and adult body mass index above or below normal are predictors for testicular cancer. From these trends, it seems fertility and cancer risk are correlated and that a number of factors can influence both. The cells commonly causing testicular cancer are called carcinoma in situ (CIS) and can be identified by several genetic markers. The same markers show similar gene expression in the testes tissue of first trimester fetuses, so it appears the CIS cancer cells originate from stem cells. A likely hypothesis is that poor function of Sertoli and Leydig cells can lead gonocytes to remain in a prolonged state as stem cells and from this testicular cancer develops. The effect is not genetic, as immigrants' sons show the pattern of their country of residence, not of ancestry. Other studies have shown a correlation between levels of organic pollutants in a mother's blood and the risk that her son will develop the cancer. Rats exposed to phthalates and environmental anti-androgens mimic the symptoms of testicular dysgenesis, including the presence of microliths in the testis. (Robert Wallace)

• Diethylstilbestrol (DES), pollution, pesticides, water, refined foods, coca cola, and white sugar, are weapons of mass destruction that make us sick by attacking us through our environment, including the womb, breast milk, the indoor home, and the outside community, said Lindsey Berkson, author and consultant, Austin, Texas. DES, the synthetic estrogen given to pregnant women from the 1940s to 1970s to prevent miscarriage, is an in utero weapon responsible for many health and reproductive problems in daughters and sons, including kidney tumors. Evidence linking renal cancer to DES exposure surfaced in the 1970s, but few studies have examined the connection. When personal experience with DES-related health problems and recent kidney cancer propelled Berkson to look into the connection, she found research linking estrogenic exposure via DES and cadmium to renal cancer and tubule failure. DES-exposed people should be aware of this risk and should get a renal ultrasound every 10 years, she suggests. (Wendy L. Hessler)

Session 4. Endocrine Disruptors: Epidemiologic Approaches
(presented by the US Environmental Protection Agency (EPA))

• Elaine Francis, US Environmental Protection Agency (EPA), Washington, DC, introduced the "Endocrine Disruptors Program Progress Review Workshop," which was sponsored by the EPA. The speakers presented results from 12 studies funded by multiple government agencies in 2000 to examine the impact of endocrine disrupting chemicals on human health and ecosystems emphasizing epidemiology approaches. The all-day session addressed a variety of health problems, exposures, and biomarkers.

• Urinary phthalate concentrations vary based upon geographic location, said Shanna H. Swan, University of Missouri, Columbia. The Study for Future Families seeks to determine the relationship between phthalate exposures and human reproductive health and if personal product use (cosmetics, perfumes, etc.) and geographic location are correlated with phthalate levels. A comparison of phthalate levels of pregnant women in rural mid-Missouri and urban Minneapolis, Minnesota, reveals that those living in Missouri have higher concentrations of phthalates in their urine. This result may be related to pesticide use, as phthalates are often used as inert ingredients in pesticides. Personal product use does not appear to be correlated with phthalate levels. Interestingly, preliminary results show that maternal phthalate levels are inversely related to paternal semen quality. The maternal levels may indicate a household exposure such as drinking water. Future objectives of this study will attempt to correlate phthalate use to infant growth and development. (Marlo K. Sellin)

• The insecticide DDT and its metabolite DDE can alter reproductive hormone levels and affect reproduction in women of childbearing age, said Xiaobin Wang, Children's Memorial Hospital Medical School, Illinois. The banned chemicals are still widely found in the environment and in humans and are suspected human reproductive toxins. To examine the link between DDT exposure and women's reproduction, researchers interviewed 466 newly married women ages 20-34 living in China. The women also kept a diary and had blood and urine samples tested for DDT and some isomers, hCG (to detect pregnancy), the urinary hormones PdG, and estrogen conjugates. DDE was found in 98 percent of the women indicating pervasive exposure. Several chemical measures showed higher exposures altered women's reproductive hormone levels and cycles. For example, women with higher DDT blood levels had lower urine levels of PdG and estrogen, earlier onset of menarche, shorter menstrual cycles, and more early pregnancy losses (less than six weeks from last menstrual period). Other preliminary, and as yet inconclusive, data suggest higher exposure may lead to lower birth weights. (Wendy L. Hessler)

• A largely Spanish-speaking, poor, and mainly immigrant population in Salinas Valley California has higher levels of several organochlorine and pesticide metabolites detected in their blood and urine than the US average. About 600 pregnant women from this area are part of a study investigating if maternal and prenatal exposure to these high levels affects fetal health and child brain development, said Laura Fenster, California Department of Health Services. Families are exposed to the chemicals either via farm fields where they work and play, through indoor house dust, or from growing up in Mexico where use of chemicals such as DDT was high. Investigators measured organochlorine pesticides (such as DDT) and PCBs in blood samples from pregnant women at 26 weeks and nonpersistent pesticides and metabolites in urine samples at 13 and 26 weeks gestation. They found DDE levels three times higher than a comparable national population. Higher levels of DDT and DDE were associated with older women and those born in Mexico. A small pilot sample found exposure to the flame retardant PBDEs at levels associated with neurotoxic effects in animals. To date, few adverse effects on fetal growth, gestation length, or neurology have been found. The study will continue to monitor the growing children's physical, mental, and emotional development as they age. This study will have the added strengths of measuring biomarkers (urine, blood, etc.) and controlling for potential confounders such as home environment issues (including lack of stimulation from toys/books, depressed mothers, and pests/peeling paint). (Wendy L. Hessler)

• Preliminary data from a continuing study suggests there may be a relationship between human blood and urine concentrations of the perfluorinated chemicals PFOS and PFOA and sperm quality, according to James Raymer, Research Triangle Institute, North Carolina. Most of us harbor these chemicals after exposure through paper food wrappers, Teflon cookware, stain-resistant sprays, and other products. To date, researchers have recruited 160 men who visited fertility clinics and have full data - questionnaire and blood/urine/semen samples - on 79 and semen data from 108. Results so far indicate that the chemicals are widely distributed and found in blood and urine but not semen. Correlations of sperm health indicators, such as volume (range 0.4 to 7.0), concentration (range 0 to 432 x 10⁶/mL), and motility (range 0 to 89 percent), indicate that semen volume decreases with increasing blood chemical concentrations. Blood concentrations, then, may be able to predict semen quality. Also unclear is if slight decreases in estrogen and possible increases in prolactin found with higher PFOS and PFOA concentrations has any real impact on semen health. (Wendy L. Hessler)

• Tongzhang Zheng, Yale University, Connecticut, discussed a case-controlled study focusing on the potential mechanism of gene-environment interaction between the CYP1A1 GST gene and PCB load on breast cancer risk. The m2 genotype more readily induces CYP1A1 activity. It increases protein levels, which may lead to higher carcinogen activation and therefore increased breast cancer risk. Postmenopausal women with the CYP1A1 m2 variant genotype had a two-fold increased risk for breast cancer compared to women with the CYP1A1 m2 homozygous wild-type genotype. Postmenopausal women with the variant genotype and higher serum PCB levels had the highest breast cancer risk with a four-fold increase. (Monica E. Unseld)

• Exposures to herbicides and fungicides seems to increase the risk of endometriosis in women of childbearing age, said Victoria Holt, Fred Hutchinson Cancer Research Center, Washington. Endometriosis affects 3 out of 1,000 US women causing chronic pain and infertility and is treated with drugs or surgery. The disease is linked to high estrogen blood levels raising concern that endocrine disrupting chemicals may increase risk. This study examined the link between endometriosis and organochlorine and PCB compounds. Self-reported data from 341 case women and 741 control women aged 18-49 found no associated increased risk from pesticides, a significant increased risk from occupational and nonoccupational exposure to herbicides, and a two- to three-fold increased risk from all exposure to fungicides. Stronger risks were associated with occupational exposure to both herbicides and fungicides. Risks did not change when genetic measures of GSTM1, COMT, and cytochrome p450 genes 1A1 and 1A2 were analyzed, indicating little if any genetic influence on endometriosis risk in these women. Blood and urine testing is ongoing for a wide variety of industrial chemicals and pesticides. Preliminary results suggest a slight increase in the mean concentrations of these pollutants in women with the disease. (Wendy L. Hessler)

• Russ Hauser, Harvard School of Public Health, Boston, Massachusetts, presented the potential reproductive and development health effects of dioxins from animal models and the clinical data, described a number of measures of adolescent growth and sexual maturation, and demonstrated effective ways to investigate the potential relationships between dioxin exposure and altered development in children. These principals were presented via a study of families living in Chapevsk, Russia. The village, located southeast of Moscow, has a significant presence of military and chemical industries. This study now includes 500 families (i.e., boys and mothers), continues to grow in size with an excellent participation rate, and includes a number of measures such as a physical exam, blood and urine samples, and a comprehensive questionnaire. From these data, maps were generated of exposure in relation to selected factories, subsequent growth curves, weight curves, and measures of body mass index. The onset of puberty and attainment of adult sex characteristics, body mass index, growth, weight, and biochemical and hormone assays identified a number of trends in the population, which has relatively elevated dioxin exposure. These data suggest a number of effective predictors for dioxin exposure and sensitivity. Diet, distance from the factories, and age were excellent predictors of dioxin exposure. This study is ongoing and is dedicated to following participants throughout development. (Gwendolyn Wood)

• Dean B. Baker, University of California at Irvine, presented preliminary data regarding reproductive and immune effects in young adults living in Oahu, Hawaii, who were prenatally exposed to the herbicide heptaclor epoxide (HE) in cow's milk. Oahu residents drank the contaminated milk for 15 months during 1981-1982 exposing pregnant women and their developing children to it. Previous studies confirmed Oahu residents have higher body HE concentrations significantly related to mother's consumption of contaminated cow's milk. A follow-up study suggested those exposed in utero had lower neurobehavioral performance, more behavior problems, and no association with school testing measures than those who were not exposed. In this new study phase, blood, urine, and semen samples from 209 Oahu-born young adults and 29 others are being examined for reproductive and immune health. Even though no strong associations have been found, hormone blood samples show slightly delayed maturity indicators and shorter menstruation in females per glass of milk drank by the mother, but no differences surfaced in antibody, cytokine activity, or other immune factors measured. Preliminary reproductive hormone data suggest anti-estrogenic effects of HE but small sample size, time from exposure, and lack of clear exposure data limit the study's conclusions. (Wendy L. Hessler)

• People living in the Slovakian town of Michalovce are surrounded by widespread PCB contamination leftover from a chemical manufacturing plant that operated there from 1959 to 1984. Even today, residents live with leaking stockpiles and polluted river water and soil used to raise chickens and pigs and to grow gardens, said Irva Hertz-Picciotto, University of California at Davis. The chronic, high-level PCB exposure is similar to Inuit Indian populations and to levels after an accident poisoned many in China. Questionnaires, teeth exams, and blood and breast milk samples at birth, 6 months, and 16 months will determine if PCB exposure affects immune and neural development. So far, 1,050 families participated at birth, 630 at 6-months, and 105 at 16-months. Data analysis is ongoing but some results are available. Blood samples at birth indicate exposure is decreasing since the 1990s but PCB levels remain high (mean of 0.689 micrograms/deciliter) compared to other populations. Higher PCB concentrations are associated with older mothers, less children, longer gestation, district where living, and eating eggs from locally grown chickens.
For more, see http://slovakchildren.ucdavis.edu/index.php. (Wendy L. Hessler)

• Pamela Imm, The Wisconsin Department of Health and Family Services, described an ongoing study examining endocrine disrupting chemicals and thyroid. The study is still in its infancy but will assess the impacts of fish consumption and polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) on human reproductive and thyroid health. Fish consumption is a leading cause of PCB exposure. This study is using participants from a 1993-94 study and a questionnaire asking about fish consumption and general health histories. A follow-up study will look at serum thyroid levels, reproductive hormone levels, and PDBE and PCB levels. (Elizabeth A. Stokes)

• Increasing rates of testicular germ cell carcinoma (TGCC) since the 1950s have some wondering if endocrine disrupting chemicals interfering with testosterone may be a factor in the disease. To investigate the risk of exposure, Steven Schwartz, Fred Huchinson Cancer Research Center, Seattle, WA, examined genes responsible for androgen synthesis, metabolism, and signaling and blood samples for DDE, PCBs, and other persistent organochlorine compounds in 140 men with the disease and 400 controls. No difference in risk was found for seven chemicals tested. However, maternal genes, specifically CYP1B1, in combination with androgen receptor antagonists like DDE, showed a two-fold increase in the risk of cancer. This suggests that who is carrying the allele - the mother or father - may be an important predictor of TGCC. (Wendy L. Hessler)

• Panel Discussion: Translation of Research into Public Health Practice and Policy. Moderator: Harold Zenick, National Health and Environmental Effects Research Laboratory, North Carolina. Panelists: R. DeLon Hull, National Institute for Occupational Safety and Health (NIOSH), Cincinnati, Ohio; LuAnn White, Center for Applied Environmental Public Health, Tulane University, New Orleans, Louisiana; Mark Dickie, University of Central Florida, Orlando; and Dan Greenbaum, Health Effects Institute (HEI), Boston, Massachusetts. Panelist discussed the need for broader distribution of publicly funded research findings to policy makers, educators, public health practitioners, public citizens, and others who may use the information in their professional and private lives. This process, called translation, involves describing how published data relates to, impacts, or otherwise fosters development of products, interventions, or policies. Although panelists agreed broader dissemination is necessary, the problems and disagreement in how best to accomplish this translation stymies the process and widens the gap between those who produce and those who need the data. Problems to overcome include: 1) the wide differences in goals and incentives between users' needs (policy decisions) and researchers (peer reviewed publishing); 2) deciding who should provide understandable and pointed summaries of findings - the researchers, intermediary third party, or others; 3) deciding who should pay and/or provide infrastructure and training; and 4) determining how to identify target audiences, best methods to present the data, and effectiveness - if translation really leads to meaningful results. The research to practice (R2P) program at NIOSH, current use of Web sites and workshops to share information, and interpretive summaries provided by HEI are examples of current efforts to translate technical research findings into information that can be used by government officials, private sector workers, and citizens. (Wendy L. Hessler)