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The insecticide 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) is still used for disease control in some areas, resulting in high levels of human exposure. The main degradation product of DDT is 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), an antiandrogen. In animal experiments, in utero exposure to DDE decreases anogenital distance in male offspring. In these models, anogenital distance serves as a measure of fetal androgen action. The authors designed the present study to examine the hypothesis that in utero exposure to DDE decreases anogenital distance in newborn human males. A cross-sectional study of 781 newly delivered male infants was conducted in 2002-2003 in Chiapas, México, where DDT had recently been used for malaria control. Measurements of anogenital distance and penile dimensions were taken, and a sample of the mother's blood was drawn. In this population, the range of serum DDE levels was large (0.8-398 microg/liter). The authors, using two-sided tests, found no evidence that exposure in utero to DDE was related to reduced androgen action as reflected by anogenital distance or penile dimensions at birth. If DDE has important antiandrogenic action in humans, it may be manifest only at higher levels of exposure or via effects on other outcomes. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether weight at birth is related to prenatal exposure to persistent organochlorine compounds.Methods: Birth weight was obtained for 197 singleton infants drawn from the general population born in two cities in Ukraine in 1993 to 1994. Concentrations of seven organochlorine pesticides (p,p'-DDT, p,p'-DDE, beta-hexachlorocyclohexane, hexachlorobenzene, trans-nonachlor, oxychlordane, heptachlor epoxide) and 11 polychlorinated biphenyl congeners measured in maternal milk taken at four or five days after birth were used as an index of prenatal exposure.Results: The greatest differences were seen for beta-hexachlorocyclohexane, with a pattern not suggestive of dose-response; infants in the lowest tertile were small, those in the central tertile were large, and those in the upper tertile were average. Adjustment for gestational age and other potential confounders had little effect on these patterns. Infants in the two upper tertiles for p,p'-DDE were larger than those in the lower tertile, with the effect being more striking after adjustment for gestational age. Adjustment for potential confounders made the pattern disappear. Other chemicals showed no convincing evidence of effects.Conclusions: Prenatal exposure to the chemicals studied, at concentrations currently seen in this population, does not impact weight at birth. [ABSTRACT FROM AUTHOR]

Breastfed children have lower risk of infectious diseases, post-neonatal mortality and chronic diseases later in life. Because epidemiologic studies usually rely on reported history of previous breastfeeding, data on the accuracy and precision of recalled histories allow improved interpretation of the epidemiologic findings. We evaluated the reliability of two reported breastfeeding durations in 567 reproductive-aged women from Mexico using information obtained from nearly identical sets of questions applied at different times after weaning. We compared differences between reports, and examined the intraclass correlation coefficient (ICC) for any and for exclusive breastfeeding (EBF). Logistic regression was used to evaluate the determinants of poor recall (difference between reports of >20%). The reliability of duration of any breastfeeding was high (ICC 0.94). Overall, differences between reports of duration were usually <1 month, and for 385/567, the difference was < or =0.5 months. Predictors of poorer recall were having > or =4 children, and time between reports of >2 months. The only predictor of better recall was greater age of the baby at weaning. The reliability of EBF duration was lower (ICC 0.49). In this population with a relatively long duration of breastfeeding, reliability of any breastfeeding duration was high. Age, education and previous breastfeeding were not important predictors of recall, in contrast to findings in earlier studies. Consistent with previous reports, however, parity and length of recall were associated with poorer recall of duration of any breastfeeding. Future studies that use reported breastfeeding duration may want to consider the effect of these variables on recall.

Dichlorodiphenyldichloroethane (DDE) and polychlorinated biphenyls (PCB) are widespread environmental contaminants that have been postulated to increase the risk of diseases such as non-Hodgkin's lymphoma, breast cancer, as well as lead to early menopause. Studies assessing the effect of organochlorine exposure often can only measure organochlorine levels once, such as at study enrollment, which may not be an etiologically relevant time period. We assessed the temporal changes in DDE and PCBs and the predictors of those changes using interview data and DDE and PCB measures collected from 123 women who were enrolled in a baseline study from 1978 to 1982 and followed up in 2003 to 2004. Baseline and follow-up organochlorine levels were compared using Spearman correlations (r(s)), and predictors of the rate of change in log concentration were evaluated using linear regression models. Although serum concentrations dramatically declined (median follow-up to baseline concentration ratio was 16% for DDE and 45% for PCB), baseline and follow-up measures were strongly correlated for DDE (r(s)=0.72) and moderately correlated for PCBs (r(s)=0.43). Prediction of follow-up PCB levels was substantially improved (r(s)=0.75) with data on initial concentration, length of lactation, baseline body mass index, and percent change in body fat, whereas DDE prediction improved slightly (r(s)=0.83) with data on lactation and baseline body mass index. These findings suggest that a single organochlorine measure provides considerable information on relative ranking at distant times and that the predictive power can be improved, particularly for PCBs, with information on a few predictors.

Background: Higher levels of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), the major degradation product of 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT), have been related to shorter duration of breast-feeding in previous studies. If DDE truly shortens lactation, this has public health importance regarding infant mortality and the use of DDT for malaria control., Objective: Our aim was to assess the relationship of maternal DDE concentrations with length of subsequent lactation., Methods: We conducted a relatively large study in a highly exposed area of Mexico. We followed 784 mother-son pairs to determine length of lactation. DDE and DDT were measured in maternal serum obtained within a day of delivery. We fit proportional hazard models with and without stratifying by previous breast-feeding, because an association of DDE with duration of lactation among those who breast-fed previously could be attributed to a noncausal mechanism., Results: Compared with those with DDE concentrations < or = 3.00 microg/g, the adjusted hazard ratios of weaning according to DDE category were, for concentrations 3.01-6.00 microg/g, 1.27 [95% confidence interval (CI), 1.04-1.55]; for concentrations 6.01-9.00 microg/g, 1.23 (95% CI, 0.92-1.63); and for concentrations > 9.00 microg/g, 1.17 (95% CI, 0.92-1.49). The corresponding ratios for women who previously breast-fed were 1.40 (95% CI, 1.06-1.87); 1.91 (95% CI, 1.24-2.93); and 1.76 (95% CI, 1.22-2.53). Those for women who had not breast-fed previously were 1.14 (95% CI, 0.86-1.52); 0.90 (95% CI, 0.61-1.31); and 0.91 (95% CI, 0.66-1.26)., Conclusions: Data from our relatively large study in a highly exposed area of Mexico did not support the hypothesis that exposure to DDE shortens length of lactation. The association seen in women who previously breast-fed was likely attributed to a noncausal mechanism. Nonetheless, whether DDT has other important adverse effects on humans is still an open question.

Development of the perineum as well as the external genitalia is determined by dihydrotestosterone, resulting in a greater anogenital distance (AGD) in males than females. In animal experiments with hormonally active agents, anogenital distance is used as a bioassay of fetal androgen action. Use of anogenital distance in human studies has been rare. Because anogenital distance has been an easy-to-measure, sensitive outcome in animal studies, we developed an anthropometric protocol for measurement of anogenital distance in human males. In this paper we describe the method for measurement of three anogenital distances, their reliability, and an assessment of predictors for each in the context of an epidemiological study. We compare the reliabilities and predictors to those for stretched penis length and penis width. A cross-sectional study of 781 newly delivered male infants was conducted in 2002-03 in Chiapas, Mexico. Replicate measures were obtained on nearly all subjects. The reliability of the measures of anogenital distance (0.82-0.91) were higher than for stretched penis length (0.78) and width (0.75). Birthweight and gestational length were more strongly related to anogenital distance than to penis length. Anogenital distance was not related to penis length (r = 0.03). Our large study clearly shows that AGD can be measured well in newborn males, and that the measurements were more reliable than those of penis length. Whether AGD measures in humans relate to clinically important outcomes, however, remains to be determined, as does its utility as a measure of androgen action in epidemiological studies.

Exposure to high levels of many pesticides has both acute and long-term neurologic consequences, but little is known about the neurotoxicity of chronic exposure to moderate pesticide levels. We analysed cross-sectional data from 18 782 Caucasian, male, licensed pesticide applicators, enrolled in the Agricultural Health Study from 1993 to 1997. Applicators provided information on lifetime pesticide use, and 23 neurologic symptoms typically associated with pesticide intoxication. Increased risk of experiencing >/=10 symptoms during the year before enrollment was associated with cumulative pesticide use, personally mixing or applying pesticides, pesticide-related medical care, diagnosed pesticide poisoning, and events involving high personal pesticide exposure. Greatest risk was associated with use of organophosphate and organochlorine insecticides. Results were similar after stratification by pesticide use during the year before enrollment, or exclusion of applicators with a history of pesticide poisoning, or high-exposure events. Use of pesticide application methods likely to involve high personal exposure was associated with greater risk. Groups of symptoms reflecting several neurologic domains, including affect, cognition, autonomic and motor function, and vision, were also associated with pesticide exposure. These results suggest that neurologic symptoms are associated with cumulative exposure to moderate levels of organophosphate and organochlorine insecticides, regardless of recent exposure or history of poisoning.

Objective: To examine the relation between prenatal 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) exposure (a metabolite of the insecticide DDT) and child growth during the first 7 years of life. Design Prospective cohort study. Participants 1,712 children born between 1959 and 1966 with measured p,p'-DDE concentrations in their mother's serum samples from pregnancy. Setting Multicenter US Collaborative Perinatal Project (CPP)., Results: The highest prenatal concentrations of p,p'-DDE (>or=60 microg/l), as compared with the lowest (<15 microg/l), were associated with decreased height at age 1 year [adjusted coefficient (SE) = -0.72 cm (0.37), n = 1,540], 4 years [-1.14 cm (0.56), n = 1,289], and 7 years [-2.19 (0.46), n = 1,371]. Among subjects in lower categories of exposure no association was observed., Conclusions: The findings suggest that high prenatal exposure to p,p'-DDE decreases height in children. Impaired growth may be a general indicator of toxicity and suggests that specific organ systems (e.g. endocrine) could be affected.

Exposure to high levels of many pesticides has both acute and long-term neurologic consequences, but little is known about the neurotoxicity of chronic exposure to moderate levels of pesticides. We analyzed cross-sectional data from 18,782 white male licensed private pesticide applicators enrolled in the Agricultural Health Study in 1993-1997. Applicators provided information on lifetime pesticide use and 23 neurologic symptoms typically associated with pesticide intoxication. An indicator of more symptoms (> or = 10 vs. < 10) during the year before enrollment was associated with cumulative lifetime days of insecticide use: odds ratios (95% confidence intervals) were 1.64 (1.36-1.97) for 1-50 days, 1.89 (1.58-2.25) for 51-500 days, and 2.50 (2.00-3.13) for > 500 days, compared with never users. A modest association for fumigants [> 50 days, 1.50 (1.24-1.81)] and weaker relationships for herbicides [> 500 days, 1.32 (0.99-1.75)] and fungicides [> 50 days, 1.23 (1.00-1.50)] were observed. Pesticide use within the year before enrollment was not associated with symptom count. Only associations with insecticides and fumigants persisted when all four pesticide groups were examined simultaneously. Among chemical classes of insecticides, associations were strongest for organophosphates and organochlorines. Associations with cumulative exposure persisted after excluding individuals who had a history of pesticide poisoning or had experienced an event involving high personal pesticide exposure. These results suggest that self-reported neurologic symptoms are associated with cumulative exposure to moderate levels of fumigants and organophosphate and organochlorine insecticides, regardless of recent exposure or history of poisoning.

Oxidation products of lipids, proteins, and DNA in the blood, plasma, and urine of rats were measured as part of a comprehensive, multilaboratory validation study searching for noninvasive biomarkers of oxidative stress. This article is the second report of the nationwide Biomarkers of Oxidative Stress Study using acute CCl4 poisoning as a rodent model for oxidative stress. The time-dependent (2, 7, and 16 h) and dose-dependent (120 and 1200 mg/kg i.p.) effects of CCl4 on concentrations of lipid hydroperoxides, TBARS, malondialdehyde (MDA), isoprostanes, protein carbonyls, methionine sulfoxidation, tyrosine products, 8-hydroxy-2'-deoxyguanosine (8-OHdG), leukocyte DNA-MDA adducts, and DNA-strand breaks were investigated to determine whether the oxidative effects of CCl4 would result in increased generation of these oxidation products. Plasma concentrations of MDA and isoprostanes (both measured by GC-MS) and urinary concentrations of isoprostanes (measured with an immunoassay or LC/MS/MS) were increased in both low-dose and high-dose CCl4-treated rats at more than one time point. The other urinary markers (MDA and 8-OHdG) showed significant elevations with treatment under three of the four conditions tested. It is concluded that measurements of MDA and isoprostanes in plasma and urine as well as 8-OHdG in urine are potential candidates for general biomarkers of oxidative stress. All other products were not changed by CCl4 or showed fewer significant effects.

Plasma and urinary levels of malondialdehyde-like products (MDA) and isoprostanes were identified as markers of in vivo lipid peroxidation in an animal model of CCl4 poisoning. We sought to determine the extent to which the formation of these oxidation products is influenced by inhibition of the cyclooxygenase enzymes which catalytically generate proinflammatory lipid peroxidation products known as prostaglandins and thromboxane. In the present studies, after induction of oxidant stress in rats with CCl4, lipid peroxidation products measured in plasma and urine demonstrate that isoprostanes and MDA can be partially inhibited by cyclooxygenase inhibitors, albeit to different extents. The lowering of isoprostane and MDA formation, however, may not to due primarily to the diminution of catalytic generation of isoprostanes or MDA by the cyclooxygenases but, rather, may be the result of the suppression of nonenzymatic lipid peroxidation. This is suggested since 8,12-iso-iPF2alpha-VI is also reduced by indomethacin, yet, unlike other isoprostanes and MDA, it is not generated catalytically by the cyclooxygenase. Thus, although the two cyclooxygenase inhibitors we tested have statistically significant effects on the measurements of both isoprostanes and MDA in this study, the results provide evidence that these lipid-degradation products primarily constitute markers of oxidative stress.

Studies of long-term effects of breastfeeding on the health of both infants and mothers often rely on maternal recall of breastfeeding duration after several decades. The authors evaluated this recall by 140 college-educated, US women 69-79 years of age who breastfed a child in 1940-1956 and recorded the duration both prospectively in a diary for the Menstruation and Reproductive History Study and retrospectively in a questionnaire in 1990-1991. Mean prospective breastfeeding duration was 5.6 months (range, 1-12 months). Mean reporting difference, questionnaire minus diary duration, was 0.0 months, with a standard deviation of 2.7 months; women who recorded short durations tended to overreport, while women who noted long durations underreported. The weighted kappa statistic for reporting agreement was 0.55 (95% confidence interval: 0.42, 0.67), with better recall observed for women in the youngest quintile at recall, firstborns, and infants with more siblings. Ever having breastfed was recalled by 94% of women. For categories of 1-3, 4-6, 7-9, and 10-12 months, recalled breastfeeding duration was correctly classified by 54% of women and was classified within +/-1 category by 89%. The observed misclassification, if nondifferential with respect to outcome, would appreciably attenuate estimates of dose-response associations between breastfeeding duration and later health.

DDT (dichlorodiphenyltrichloroethane), a pesticide once used widely in agriculture and now limited to public health use, remains a controversial chemical because of a combination of benefits and risks. DDT or its breakdown products are ubiquitous in the environment and in humans. Compounds in the DDT family have endocrine actions and have been associated with reproductive toxicity. A previous study reported associations between prenatal exposure to p,p -DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene] and increased height and weight in adolescent boys. We examined a group with higher exposures to see whether similar associations would occur. Our study group was 304 males born in Philadelphia in the early 1960s who had participated in a previous study. Anthropometric and pubertal measures from one to six visits during their adolescent years were available, as were stored maternal serum samples from pregnancy. We measured p,p -DDE, p,p -DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)-ethane], and o,p -DDT [1,1,1-trichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)-ethane] in the maternal serum. Outcomes examined in the boys were height, ratio of sitting height to height, body mass index, triceps skinfold thickness, ratio of subscapular to the sum of triceps and subscapular skinfold thicknesses, skeletal age, serum testosterone, and serum dehydroepiandrosterone sulfate. No associations between prenatal exposure to any of the DDT compounds and any outcome measure were seen.

Objective: We compared rates of total and spontaneous preterm birth in Avon County, England and urban Ukraine to explore whether adverse conditions in the former eastern bloc influenced the preterm rate., Study Design: Women who had last menstrual period (LMP) in a specified time window were recruited from geographically defined areas. Data were gathered between 1992 and 1995, using maternal questionnaires and medical record abstraction, with comparable methods in both sites insofar as possible. There were 13731 births in Avon and 3087 in Ukraine. Rates of total and spontaneous preterm births were compared, taking account of maternal characteristics and other relevant variables., Results: The total preterm birth rates were similar (5.9%, Ukraine; 5.5%, Avon) but the spontaneous preterm rate was about 60% higher in Ukraine (5.0% versus 3.1%). Maternal characteristics and measurement differences did not explain the discrepancy., Conclusion: The difference in the spontaneous preterm rates may reflect differences in obstetrical management resulting from shortages of medical supplies and equipment in Ukraine.

Farmworkers experience many work-related hazards, including exposure to neurotoxicants. We compared neurobehavioral performance of 288 farmworkers in central Florida who had done farm work for at least 1 month with 51 controls who had not. Most of the farmworkers had worked in one or more of three types of agriculture: ornamental ferns, nurseries, or citrus fruit. We collected information on farm work history in a structured interview and evaluated neurobehavioral performance using a battery of eight tests. Analyses were adjusted for established confounders including age, sex, education, and acculturation. Ever having done farm work was associated with poor performance on four tests--digit span [odds ratio (OR) = 1.90; 95% confidence interval (CI), 1.02-3.53], tapping (coefficient = 4.13; 95% CI, 0.00-8.27), Santa Ana test (coefficient = 1.34; 95% CI, 0.29-2.39), and postural sway (coefficient = 4.74; 95% CI, -2.20 to 11.7)--but had little effect on four others: symbol digit latency, vibrotactile threshold, visual contrast sensitivity, and grip strength. Associations with farm work were similar in magnitude to associations with personal characteristics such as age and sex. Longer duration of farm work was associated with worse performance. Associations with fern work were more consistent than associations with nursery or citrus work. Deficits related to the duration of work experience were seen in former as well as current farmworkers, and decreased performance was related to chronic exposure even in the absence of a history of pesticide poisoning. We conclude that long-term experience of farm work is associated with measurable deficits in cognitive and psychomotor function.

Humans are always exposed to mixtures of polychlorinated biphenyls (PCBs), so assessment of their health effects is complicated. Because the original sources are relatively standard mixtures that change in predictable ways while traversing the environment, there is substantial uniformity in the congener mixtures people carry. To the extent that concentrations are highly correlated, measuring multiple congeners within correlated groups would be unnecessary and estimation of separate biologic effects would be impossible. We examined correlation patterns in previously collected data on 38 congeners (and 14 other organochlorines) from 497 human milk samples from Canada from 1992. Congeners 138, 153, 156, 157, 170, 183, 187, 194, 199, and 203 were highly intercorrelated; 180 had slightly lower correlations with this group. Congeners 74, 105, and 118 were highly intercorrelated and moderately to highly correlated with the first group. Congener 99 had moderate correlations with both these groups, and congener 66 had lesser correlations with the primary group. In contrast, congeners 28, 44, 49, 60, 90/101, 128, 137, and 193 showed little correlation with any other congeners. The remaining 14 congeners were uninformative; they were quantified in fewer than 30% of samples, and varying lipid concentrations meant that those quantified were not necessarily at higher concentrations than those not quantified. In study of human health effects of PCBs, the congener pattern present in the population under study should be examined when deciding which congeners to measure; instead of solely redundant or uninformative congeners, attention should be given to other congeners that may be more useful in addressing the question of interest.

Background: Placental weight and its ratio to birthweight have recently been reported to predict later chronic disease. These fetal growth indicators have been measured in the west for over a century with consistent results when methods of preparation were comparable. We investigated whether recent difficult conditions in the former eastern bloc have altered placental weight or its relationship to other fetal size measures from what has historically been reported., Methods: Placentas were obtained from 1621 singleton births of at least 28 weeks gestation in a Ukrainian city during 1993-1994, using a systematic protocol. Maternal characteristics were obtained from questionnaires. Pregnancy complications and birth size measures (infant weight, length, crown-rump length, and head circumference) were abstracted from medical records. We examined relationships of placental weight and ratio to these variables., Results: Placental weight ranged from 100 to 1000 g, with a mean of 470 g. Mean placental ratio was 13.9%. Placental weights increased and ratios decreased with gestational age. Larger ratios were related to larger maternal BMI. Absolute measures of infant size and placental weight were mutually positively correlated. Placental ratio, infant length, and ponderal index (PI) were nearly uncorrelated., Conclusions: Absolute and relative weights of Ukrainian placentas were similar to historical reports, as were their relationships to other infant size indicators. Placental weight ratio (PWR), ponderal index, and infant length measured different birth size dimensions. Placental availability, consistency of placental measurements, and placental ratio's reflection of an independent facet of fetal growth make the placenta a useful research tool.

Polychlorinated biphenyls (PCBs) are persistent pollutants that are ubiquitous in the food chain, and detectable amounts are in the blood of almost every person in most populations that have been examined. Extensive evidence from animal studies shows that PCBs are neurotoxins, even at low doses. Interpretation of human data regarding low-level, early-life PCB exposure and subsequent neurodevelopment is problematic because levels of exposure were not similarly quantified across studies. We expressed the exposure levels from 10 studies of PCB and neurodevelopment in a uniform manner using a combination of data from original investigators, laboratory reanalyses, calculations based on published data, and expert opinion. The mainstay of our comparison was the median level of PCB 153 in maternal pregnancy serum. The median concentration of PCB 153 in the 10 studies ranged from 30 to 450 ng/g serum lipid, and the median of the 10 medians was 110 ng/g. We found that (a)) the distribution of PCB 153 exposure in most studies overlapped substantially, (b)) exposure levels in the Faroe Islands study were about 3-4-fold higher than in most other studies, and (c)) the exposure levels in the two recent U.S. studies were about one-third of those in the four earlier U.S. studies or recent Dutch, German, and northern Québec studies. Our results will facilitate a direct comparison of the findings on PCBs and neurodevelopment when they are published for all 10 studies.

Hospital admissions are generally regarded as a marker of severe pregnancy complications, and a low ratio of antenatal admissions to deliveries is considered an indicator of maternal-fetal well-being. We investigated the reasons for hospital admissions in a sample of deliveries from Ukraine, a country of the former eastern bloc. All hospitalisations were traced among 3099 women who delivered live singletons of at least 20 weeks gestation in two urban areas of Ukraine and data were abstracted from their medical records. More than a third of the women were admitted to hospital during their pregnancy, and 91% of the admissions were for a pregnancy complication, primarily threatened abortion or early labour. Median length of stay for all admissions was 12 days. The ratio of admissions to deliveries was 52 per 100. The Ukrainian ratio of hospitalisations to deliveries is notably higher than any that have been published in studies from the United States and Australia, reflecting patterns of care that stress hospital-based treatment. This high ratio does not necessarily mean that Ukrainian women are sicker, although that may be the case. The comparison of hospitalisation to delivery ratios is meaningful only when other factors, such as resources, patterns of care, costs and access, are taken into account.

This article describes a procedure for the quantitation of the isoprostane 15-F2t-IsoP (9a,11a,15S-trihydroxy-(8b)-prosta-5Z,13E-dien-1-oic acid [CAS#27415-26-5] formerly known as 8-epi-PGF2a or 8-iso-PGF2a, and also as iPF2a-III). We have combined features from several earlier methods for 15-F2t-IsoP and prostaglandins, and identified and modified those steps that may lead to poor recoveries. The resulting protocol is precise and reliable, and was validated by a blind time-course study of plasma levels in rats treated with 120 and 1200 mg CCl4/kg body weight. Plasma levels of 15-F2t-IsoP, as measured according to the procedure described above, are good indicators of acute oxidative stress as induced by CCl4. The precision of the measurements allows detection of elevated plasma 15-F2t-IsoP levels as long as 16 h after an acute exposure of 120 mg CCl4/kg body weight, and 2 h after an exposure of 1 mg CCl4/kg body weight. The results of this low-dose, pilot study suggest that this method has sufficient analytical precision to allow the detection of the small changes in plasma isoprostane levels, which result from chronic and/or lower-level exposures to agents causing oxidative stress.

The economic, social and health problems faced by former eastern bloc countries after the demise of the Soviet Union are unique in the recent history of Europe. We conducted a study in two urban areas of Ukraine, asking if the traditional predictors of preterm delivery continue to be associated with risk under these conditions. Subjects were pregnant women with last menstrual period (LMP) between 25 December 1992 and 23 July 1994. Self-completed questionnaires and the medical record provided data. We compared 137 spontaneous preterm deliveries with 2,886 full-term births, using all established risk factors for which we had data. Maternal age was the variable most strongly related to preterm birth. Being 18 or less had an odds ratio (OR) of 3.7; being 30+ had an OR of 2.5 relative to the reference group of age 25-29. Placental complications and pre-existing hypertension had ORs of 2.7 and 2.3, respectively, but the confidence interval included 1.0. Low net pregnancy weight gain (less than 10 kg) was significantly associated with preterm birth, but the rate of net weight gain was not. Marital status and educational category were only weakly related. We conclude that although Ukraine faced serious difficulties during its transition to a market economy, these problems did not generally alter the outcome of pregnancy in our sample when the classic risk factors for preterm delivery were present.

Concentrations of chrysene, benz [a] anthracene, benzo [a]-pyrene, benzo [b] fluoranthene, indeno [1,2,3-c,d] pyrene, dibenz [a,h] anthracene, and benzo [g,h,i] perylene were measured in placentas from 200 women from two cities in Ukraine, Kyiv and Dniprodzerzhinsk. The participants had no special exposures and were chosen from among subjects in an ongoing study of reproductive health. All seven of the polycyclic aromatic hydrocarbons (PAHs) were found in all placentas, with the sole exception of benzo [a] pyrene in one placenta. Chrysene was present at the highest concentrations, with median 1.38 ng/g dry weight. Dibenz [a,h] anthracene and benzo [g,h,i] perylene had the lowest concentrations; each had median 0.73 ng/g dry weight. Concentrations in Kyiv were slightly higher than those in Dniprodzerzhinsk, but the difference was significant only for dibenz [a,h] anthracene. Dibenz [a,h] anthracene and benzo [g,h,i] perylene increased significantly with maternal body mass index, but other PAHs showed no such pattern. Placentas from deliveries in autumn or winter had slightly but not significantly higher concentrations. Concentrations were not related to maternal age. There were too few smokers in the sample for meaningful evaluation. No associations were seen between any of the placental PAH concentrations and birth weight of the infant.

Ukraine is a highly industrialized country with major environmental problems and deteriorating reproductive health. Heavy metals are known reproductive toxins; a study was undertaken to determine whether they were present at sufficient concentrations to be playing a major role in these health problems. Placental concentrations of arsenic, cadmium, copper, lead, mercury, and zinc were determined in 200 women from the general population of two urban areas of Ukraine, Kyiv and Dniprodzerzhinsk. Arsenic was detected in only 5% of the samples, lead in 22%, and mercury in 28%. Cadmium was detected in almost all samples, with a median of 5.2 ng/g. Concentrations of lead, mercury, and cadmium were low compared to those reported elsewhere, while zinc and copper concentrations were comparable.

Background: Retinal degeneration is the leading cause of visual impairment in older adults, but little is known about its relationship to neurotoxic exposures., Methods: The Agricultural Health Study is a cohort study of licensed pesticide applicators from Iowa and North Carolina. We used cross-sectional data from self-administered questionnaires given at enrollment in 1994-1996 to compare pesticide use in 154 applicators who reported retinal degeneration and 17,804 controls., Results: Retinal degeneration was associated with fungicide use (odds ratio = 1.8, 95% confidence interval = 1.3-2.6). This relationship was seen in subgroups defined by state, demographic characteristics, or medical history, as well as in the entire group. Risk increased with cumulative days of fungicide use (P for trend = 0.011) and was greater when application methods involving greater personal exposure were used. Retinal degeneration was also related to use of organochlorine or carbamate insecticides, but these associations were less consistent. Since nearly all applicators used organophosphate insecticides and herbicides, these exposures could not be effectively evaluated., Conclusions: These results suggest that exposure to some fungicides and insecticides may increase risk of retinal degeneration., (Copyright Published 2000 Wiley-Liss, Inc.)

Objective: To determine whether the preterm birth rate was elevated in two urban areas of Ukraine, a former eastern bloc country that experienced serious economic, social, and health problems during its transition from a socialist republic., Methods: We identified every pregnancy in a defined period in two urban sites where a separate study of pregnancy and childhood was being conducted. We obtained gestational age and vital status at delivery for each. Information about onset of labor and conduct of delivery was available for the subgroup enrolled in the collaborating study., Results: Among 17,137 pregnancies, all but 6774 were terminated voluntarily. Among the continuing pregnancies, the preterm birth rate was 6.6% for live-born singletons of 20 or more weeks' gestation. Only 12% of preterm births involved medical intervention, the rest were idiopathic. The preterm birth rate was higher than in Europe (4.0% to 5.4%) and Canada (5.9%) but lower than for whites in the United States (8.4%)., Conclusion: Live-born preterm birth rates are influenced by whether infants survive to be included in calculations. The high fetal mortality rate in Ukraine causes many preterm births to be excluded, thus lowering the rate. Frequent pregnancy termination and lack of ultrasound dating in Ukraine also might cause the preterm birth rate to be lower. Preterm birth rates, especially among live-born infants, are difficult to interpret and treacherous to compare across nations. Survival of the fetus and its health and development at birth are better indicators of reproductive outcome.

Polychlorinated biphenyls (PCBs) are industrially produced environmentally persistent compounds. In developed countries all humans have detectable levels in blood and other tissues. PCBs alter thyroid hormone metabolism in animal experiments, and human data suggest background-level exposure may have similar effects in neonates. We evaluated this possible effect among 160 North Carolina children whose in utero PCB exposure was estimated on the basis of the mother's PCB levels in milk and blood, in 1978-1982 (estimated median PCB level in milk at birth, 1.8 mg/kg lipid). Their umbilical cord sera were thawed in 1998 and assayed for total thyroxine, free thyroxine, and thyroid stimulating hormone. We found that PCB exposure was not strongly related to any of the thyroid measures. For example, for a one unit change in milk PCB concentration (mg/kg lipid), the associated multivariate-adjusted increase in thyroid stimulating hormone level was 7% (95% confidence limits (CL) = -6, 21). Despite the possibility of sample degradation, these data suggest that within the range of background-level exposure in the United States, in utero PCB exposure is only slightly related to serum concentration of total thyroxine, free thyroxine, and thyroid stimulating hormone at birth.

In studies of the potential health effects of background-level exposure to organochlorine compounds (e.g., polychlorinated biphenyls, polychlorinated dibenzodioxins, and polychlorinated dibenzofurans), investigators have often measured either polychlorinated biphenyls or polychlorinated dibenzodioxins/polychlorinated dibenzofuransbut not both. We measured polychlorinated biphenyls (including specific non-, mono-, and di-ortho congeners) and specific polychlorinated dibenzodioxins/dibenzofurans among 63 Canadian blood donors. Levels of these compounds were, in general, fairly correlated. For example, Pearson's correlation coefficient between log total polychlorinated biphenyl and log total polychlorinated dibenzodioxins was .52. These results suggest that in epidemiologic studies of health effects of background-level exposures to these compounds, the quantitative dose-response relation observed for a given compound (or class of compounds acting through a similar mechanism) may easily be miscalibrated or confounded.

Objectives: Polychlorinated biphenyls (PCBs) and dichlorodiphenyl dichloroethene (DDE) are ubiquitous toxic environmental contaminants. Prenatal and early life exposures affect pubertal events in experimental animals. We studied whether prenatal or lactational exposures to background levels of PCBs or DDE were associated with altered pubertal growth and development in humans., Study Design: Follow-up of 594 children from an existing North Carolina cohort whose prenatal and lactational exposures had previously been measured. Height, weight, and stage of pubertal development were assessed through annual mail questionnaires., Results: Height of boys at puberty increased with transplacental exposure to DDE, as did weight adjusted for height; adjusted means for those with the highest exposures (maternal concentration 4+ ppm fat) were 6.3 cm taller and 6.9 kg larger than those with the lowest (0 to 1 ppm). There was no effect on the ages at which pubertal stages were attained. Lactational exposures to DDE had no apparent effects; neither did transplacental or lactational exposure to PCBs. Girls with the highest transplacental PCB exposures were heavier for their heights than other girls by 5.4 kg, but differences were significant only if the analysis was restricted to white girls., Conclusions: Prenatal exposures at background levels may affect body size at puberty.

Antioxidants in the blood plasma of rats were measured as part of a comprehensive, multilaboratory validation study searching for noninvasive biomarkers of oxidative stress. For this initial study an animal model of CCl(4) poisoning was studied. The time (2, 7, and 16 h) and dose (120 and 1200 mg/kg, intraperitoneally)-dependent effects of CCl(4) on plasma levels of alpha-tocopherol, coenzyme Q (CoQ), ascorbic acid, glutathione (GSH and GSSG), uric acid, and total antioxidant capacity were investigated to determine whether the oxidative effects of CCl(4) would result in losses of antioxidants from plasma. Concentrations of alpha-tocopherol and CoQ were decreased in CCl(4)-treated rats. Because of concomitant decreases in cholesterol and triglycerides, it was impossible to dissociate oxidation of alpha-tocopherol and the loss of CoQ from generalized lipid changes, due to liver damage. Ascorbic acid levels were higher with treatment at the earliest time point; the ratio of GSH to GSSG generally declined, and uric acid remained unchanged. Total antioxidant capacity showed no significant change except for 16 h after the high dose, when it was increased. These results suggest that plasma changes caused by liver malfunction and rupture of liver cells together with a decrease in plasma lipids do not permit an unambiguous interpretation of the results and impede detection of any potential changes in the antioxidant status of the plasma.

Objectives: Frequent terminations of pregnancy and high rates of fetal loss have been reported, but not confirmed, in the former eastern bloc. A census of pregnancies in Ukraine, a former eastern bloc country, was conducted to determine the rates of these events., Methods: All pregnancies registered in 2 urban areas were enumerated. During a 19-month period between 1992 and 1994, 17,137 pregnancies and their outcomes were recorded., Results: Sixty percent of the pregnancies were voluntarily terminated, generally before the 13th week. In pregnancies delivered at 20+ weeks, fetal mortality was 29 per 1000, nearly 5 times the rate among Whites in the United States. There was a greater proportion of very early deliveries (20-27 weeks) in Ukraine, as well as higher death rates at all gestational ages. Perinatal mortality was estimated to be 35 per 1000, about 3 times the US rate., Conclusions: This is believed to be the first study in the former eastern bloc to ascertain all of the clinically recognized pregnancies in a specified period and to determine their outcomes. The data document elevated reproductive risks in a former Soviet state.

Substantial environmental pollution has been alleged in Ukraine, but little information is available to allow an assessment of the possible impact on humans. To help remedy this lack of information, it was of interest to investigate whether certain polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), or coplanar polychlorinated biphenyls (PCBs) were elevated in people from Ukraine. Samples of breast milk were obtained from 200 women from the cities of Kyiv and Dniprodzerzhinsk; Kyiv is the capital and Dniprodzerzhinsk is a highly industrialized city. The samples were combined into four pools by city and age, and analyzed for 7 PCDDs, 10 PCDFs, and 2 coplanar PCBs (126 and 169). The total of the measured PCDDs, expressed as toxic equivalent, ranged from 5.1 to 7.6 pg/g lipid; for PCDFs from 3.6 to 5.2, and for PCBs from 11 to 18 pg/g lipid. Results from the two cities were similar; older women had slightly higher concentrations than did younger women. Levels of these compounds seen in Ukraine were similar to or lower than those seen in other recent studies from European and Asian countries.

The literature on lipid peroxide levels in uncomplicated pregnancy is limited, but some reasonable conclusions are possible. Despite the lack of precision in the predominant measure of lipid oxidation, there is agreement across a large number of studies that the level of lipid peroxides in blood is generally higher in pregnant women than in nonpregnant women. During gestation, elevations appear by the second trimester and may taper off later in gestation, decreasing further after delivery. Lipid peroxides also are produced in placenta, but their pattern of change over the course of pregnancy is unclear. Lipid peroxides are important because their uncontrolled production can result in oxidative stress, with significant damage to cell integrity. There is a growing literature that associates oxidative stress with preeclampsia, a major cause of maternal and fetal morbidity. The higher levels of lipid peroxides seen in blood and the production of lipid peroxides in the placenta, even in uncomplicated pregnancies, make new baseline studies a priority. These studies should include measurements of lipids and blood volume, because they can influence marker values, with sensitive and specific measures of lipid peroxidation made at various points of gestation. From our review of the existing literature we conclude that the importance of oxidative stress in reproduction is just beginning to be appreciated and studied.

Reports of environmental problems in the former Soviet Union, including excess use of pesticides, have led to concerns about high levels of contamination in humans, but little information is available to assess whether these concerns are warranted. Samples of breast milk from 197 women from two cities in Ukraine were analyzed for p,p'-DDT, p,p'-DDE, endrin, dieldrin, heptachlor epoxide, trans-nonachlor, oxychlordane, hexachlorobenzene, ss-hexachlorocyclohexane (HCH), and 18 polychlorinated biphenyl congeners, and results were compared to previous reports from Europe. The median ss-HCH concentration was 731 ng/g milk fat, which is higher than other reports from Europe but lower than reports from other parts of the world. The median DDE concentration was 2,457 ng/g milk fat, which is higher than most but not all other reports from Europe. Concentrations of other chemicals were comparable to or lower than other reports from Europe. Concentrations from the city of Kyiv were generally lower than those from Dniprodzerzhinsk, but the magnitudes of these differences were modest.

In utero exposure to dichlorodiphenyldichloroethene and polychlorinated biphenyls, within the range found in the general U.S. population, may produce detectable effects in offspring. To design studies of the effects of in utero organochlorine exposure, we obtained data on the relationship between gestational and perinatal maternal levels in females on several occasions. We studied 67 pregnant women in the United States who agreed to have their blood drawn once during each trimester and once postpartum. We examined the Pearson correlation coefficient between the natural logarithm of levels (microg/g serum lipid). The correlation, r, among levels in the first and third trimester was .86 and .77 for dichlorodiphenyldichloroethene and for polychlorinated biphenyls. Correlations among levels determined at other times (i.e., second trimester and postpartum) were similar. On the basis of these results, we suggest that in studies of the effects of in utero or perinatal exposure to the aforementioned compounds, the time when specimens are collected is not critical.

Background: Correlations among human levels of polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins, and polychlorinated dibenzofurans potentially complicate interpretation of studies of their individual health effects. Outcomes attributed to one may, in fact, be due to another., Methods: We present correlations among dioxins, furans, and PCBs in blood collected in 1991-1992 from 44 American Vietnam veterans from Michigan., Results: Correlations among specific dioxins and furans ranged from 0.26 to 0.80, with the higher-chlorinated congeners being more highly correlated. Correlations among PCBs ranged from 0.06 to 0.94, with those occurring at highest concentrations being more highly correlated. Correlations of PCBs with dioxins and furans ranged from -0.09 to 0.59. Correlations of individual chemicals with total dioxin toxic equivalents ranged from 0.31 to 0.76., Discussion/conclusions: If confirmed in other populations, such correlations may allow the use of simpler assays but may also raise issues of confounding and calibration.

Lipid peroxidation is thought to be important in numerous disease states, including pregnancy complications. Study of its role requires markers, but the variability of available markers in non-diseased populations has not been well-characterized. We examined the variability over time of blood lipid hydroperoxides, as measured by iodometric analysis, in 49 healthy young women, 21 nonpregnant and 28 pregnant. Lipid hydroperoxides from the same woman were very similar from one day to the next but were less stable over periods of a month or more. The correlation between measurements on consecutive days was 0.98; the correlation between measurements a month or more apart was 0.11. Variability over time was not attributable to seasonal effects or, among the pregnant women, to differences over the course of pregnancy. Knowledge of the variability of this and other markers of oxidative damage enables the development of appropriate study designs.

Background: Families of farmer pesticide applicators have unusual opportunities for exposure, directly or indirectly, to pesticides. These exposures are not well characterized., Methods: Subjects were 26,793 licensed private pesticide applicators enrolled in the Agricultural Health Study, a cohort study being conducted in Iowa and North Carolina. Questionnaires were completed by the applicators and their spouses., Results: Many indirect exposure opportunities exist; for example, 21% of homes are within 50 yards of pesticide mixing areas, 27% of applicators store pesticides in their homes, and 94% of clothing worn for pesticide work is washed in the same machine as other laundry. Direct exposure opportunities also occur; for example, 51% of wives of applicators worked in the fields in the last growing season, 40% of wives have ever mixed or applied pesticides, and over half of children aged 11 or more do farm chores., Discussion/conclusions: The extent of the opportunities for exposure of family members of farmer pesticide applicators makes studies of their health important.

The reproductive system of male mice homozygous for a mutation in the estrogen receptor (ER) gene (ER knock-out; ERKO) appears normal at the anatomical level. However, these males are infertile, indicating an essential role for ER-mediated processes in the regulation of male reproduction. Adult ERKO male mice have significantly fewer epididymal sperm than heterozygous or wild-type males. Although spermatogenesis is occurring in some seminiferous tubules of 3- to 5-month-old ERKO males, other tubules either have a dilated lumen and a disorganized seminiferous epithelium with few spermatogenic cells or lack a lumen and contain mainly Sertoli cells. There are no obvious differences in seminiferous tubules at 10 days of age between wild-type and ERKO mice, but the lumen in ERKO males is dilated in all seminiferous tubules by 20 days. However, spermatogenesis progresses and similar numbers of sperm are present in the cauda epididymis of ERKO and wild-type males until 10 weeks of age. Disruption of spermatogenesis and degeneration of the seminiferous tubules become apparent after 10 weeks in the caudal pole of the testis and progresses in a wave to the cranial pole by 6 months. However, the seminal vesicles, coagulating glands, prostate, and epididymis do not appear to be altered morphologically in ERKO mice. Serum testosterone levels are somewhat elevated, but LH and FSH levels are not significantly different from those in wild-type males. Sperm from 8- to 16-week-old mice have reduced motility and are ineffective at fertilizing eggs in vitro. In addition, ERKO males housed overnight with hormone-primed wild-type females produce significantly fewer copulatory plugs than do heterozygous or wild-type males. These results suggest that estrogen action is required for fertility in male mice and that the mutation of the ER in ERKO males leads to reduced mating frequency, low sperm numbers, and defective sperm function.

Arsenic is a known teratogen and developmental toxicant in many animal models. The aim of the present study was to determine the influence of arsenic oxidation state, concentration, duration of exposure, and embryonic gestational age on arsenic-induced developmental toxicity. For these studies whole embryo culture was used since this experimental model allows an assessment of the direct effect of the toxicant on the embryo and precise control of the variables of interest. ICR and CD1 mouse embryos were prepared for whole embryo culture and exposed to concentrations of trivalent (1, 2, 5, 7.5, 10, 20, and 30 microM of sodium arsenite) and pentavalent arsenic (5, 10, 20, 50, and 100 microM of sodium arsenate) at different developmental stages (3, 4-6, 8-10, or 20-23 pairs of somites) and for different exposure periods (1, 4, 6, or 24 hr). Embryonic growth, development, malformation rates, and viability were evaluated. A comparison of the ED50s of the two oxidation states showed that arsenite was about three times more potent than arsenate with respect to both malformations and lethality. The pattern of malformations was similar for both arsenite and arsenate and involved nonclosure of the cranial neural tube, prosencephalic hypoplasia, dysmorphogenesis of the optic and otic anlagen, and pharyngeal arch defects. ICR conceptuses were more sensitive than CD1s with regard to perturbation in embryonic growth by both forms of arsenic. ICRs were also more sensitive to otic, pharyngeal arch, and somite dysmorphogenesis induced by arsenite. With increasing gestational age there was an increasing resistance to arsenic-induced effects. In comparison to the 4-6 somite stage, the ED50 for induction of dysmorphogenesis was increased about twice at the 8-10 somite and over three times in 20-23 somite stage embryos. Exposure to arsenite/arsenate for a 1-hr period was sufficient to induce maldevelopment. A 6-hr exposure induced prosencephalic, otic, and optic abnormal development at a rate similar to that produced by a 24-hr exposure. The malformation pattern produced by exposure to arsenite/arsenate in vitro closely corresponds to that produced by maternal administration at the same gestational stage. This indicates that the arsenic embryopathy may be the result of a direct impact of the agent on the conceptus.

Background: If pair members are independent, simple matched-pair case-control studies are known to yield consistent estimates of the population odds ratio. If pair members are not independent, this is not necessarily true. It has been shown previously that the usual matched-pair estimate remains consistent if the exposure of interest is correlated within the pairs. However, the effect of correlation of unmeasured risk factors within the pairs has not been studied., Methods: We examine the effect of within-pair correlation of unmeasured risk factors independent of the measured exposure. This is done within the context of a simple matched-pair case-control study. We compare the large-sample expectation of the usual matched-pair estimate to the population odds ratio., Results: We show that the usual estimate may be inconsistent in the presence of this correlation. However, if the disease is rare, the magnitude of the bias will be negligible., Conclusions: Correlation of unmeasured risk factors independent of the measured exposure is not a practical problem in this setting.

Objectives: Worldwide declines in the duration of lactation are cause for public health concern. Higher levels of dichlorodiphenyl dichloroethene (DDE) have been associated with shorter durations of lactation in the United States. This study examined whether this relationship would hold in an agricultural town in northern Mexico., Methods: Two hundred twenty-nine women were followed every 2 months from childbirth until weaning or until the child reached 18 months of age. DDE was measured in breast milk samples taken at birth, and women were followed to see how long they lactated., Results: Median duration was 7.5 months in the lowest DDE group and 3 months in the highest. The effect was confined to those who had lactated previously, and it persisted after statistical adjustment for other factors. These results are not due to overtly sick children being weaned earlier. Previous lactation lowers DDE levels, which produces an artifactual association, but simulations using best estimates show that an effect as large as that found here would arise through this mechanism only 6% of the time., Conclusions: DDE may affect women's ability to lactate. This exposure may be contributing to lactation failure throughout the world.

The probability that conception will result from intercourse on particular days of the menstrual cycle is of biological, demographic, and personal interest to many. We describe an existing model for conception as related to the timing of intercourse, and develop a method for fitting it by means of the expectation-maximization (EM) algorithm, using widely available software (GLIM). We then generalize the model to allow for effects on its parameters due to reproductively toxic exposures. A further extension allows one to address the question of whether the pattern of intercourse in a conception cycle has an influence on the sex of the resulting baby. We illustrate the methods by application to data from a prospective study of couples trying to begin a pregnancy.

Objectives: The relationship of behavior and activity levels to the interval between outbreak and year of birth and to age of children is explored in Taiwanese children exposed in utero to heat-degraded polychlorinated biphenyls (PCBs)--the Yu-cheng children. Additionally, the relationship of the scores to chemical, physical, and cognitive findings is described., Methods: With Rutter's Child Behavior Scale A and a modified Werry-Weiss-Peters Activity Scale, 118 Yu-chen children and matched controls were followed biannually from 1985 to 1991., Results: At each year, the Yu-cheng children scored 7% to 43% worse (mean = 23%) than control children on the Rutter scale. At any fixed age, the Yu-cheng children scored 11% to 63% (mean = 28%) worse. The effect for children born later did not differ from that for those born earlier; neither was there any improvement as the children aged. A similar but weaker picture was seen for the activity score. These behavioral findings were not related to physical or cognitive findings or to serum PCB levels., Conclusions: In utero exposure to heat-degraded PCBs appears to cause mildly disordered behavior and increased activity level; the effect persists over time and is similar in children born up to 6 years after the mothers were exposed.

High-dose boric acid (BA) produces testicular lesions in adult rats, characterized by inhibited spermiation followed by atrophy. The present study addressed whether inhibited spermiation can be separated from atrophy based on dose, compared testis boron (B) dosimetry to lesion development, determined how inhibited spermiation was reflected by common reproductive endpoints, and examined reversibility of the testicular lesions. Rats were fed 3000, 4500, 6000, or 9000 ppm BA for up to 9 weeks and examined. Recovery was assessed for up to 32 weeks post treatment. Inhibited spermiation could be separated from atrophy based on dose (inhibited spermiation: 3000/4500 ppm; atrophy: 6000/9000 ppm), with each lesion aspect expressed at different threshold testis B concentrations (inhibited spermiation: 5.6 micrograms B/g and atrophy: 11.9 micrograms B/g) with no B accumulation during the 9-week exposure. These data suggest that separate mechanisms may be operating for these lesion aspects based on testis B concentration and that B dose rate was important for testicular toxicity. Inhibited spermiation was most reliably reflected by informed testicular histology, with the more severe cases decreasing epididymal sperm count to levels that could affect fertility. After treatment, serum and testis B levels in all dose groups rapidly fell to background levels at the earliest time points evaluated (7 days and 8 weeks posttreatment, respectively). The severely inhibited spermiation at 4500 ppm was resolved by 16 weeks posttreatment, but areas of focal atrophy were detected that did not recover posttreatment. Also, no signs of recovery from atrophy were observed (6000 and 9000 ppm). Atrophic tubules contained a normal complement of spermatogonia (2.6 to 2.9 germ cells/100 Sertoli cells), with occasional dividing and degenerating germ cells. Elevations in serum FSH and LH levels suggested an intact hormonal response to the atrophy. In summary, 1) the different aspects of the BA-induced testicular lesion can be separated using different doses, 2) inhibited spermiation does not necessarily proceed to atrophy, and 3) there is no recovery from the atrophy despite the absence of testis B after treatment. The ability to separate inhibited spermiation from atrophy based on dose and testis B dosimetry will be useful in evaluating possible mechanisms. Furthermore, the presence of dividing spermatogonia during long-term BA-induced atrophy suggests that this model should be useful for identifying critical components involved in the reinitiation of spermatogenesis.

Eight-hundred fifty-five newborns were enrolled in a prospective study between 1978 and 1982 and then followed through school age. To determine whether the mode of infant feeding affected developmental scores or school grades, prospective data were collected on how the children were fed; 788 of the children had Bayley tests at 6 months, 720 at 12 months, 676 at 18 months and 670 at 2 years. McCarthy testing was done on 645 children at 3 years, 628 at 4 years and 636 at 5 years. Testers were not specifically blind to feeding method. The families provided report cards from grade 3 or higher for 366 children. There were statistically significant but small increases in scores among breast-fed children on at least some subscales of the Bayley and McCarthy at all time points from 2 years through 5 years and slightly higher English grades on report cards in both crude analyses and in multivariate analyses that allowed adjustment for the most plausible confounding variables. We conclude that, in a volunteer, 95% white sample of middle class children, those breast-fed scored slightly better than those bottle fed; the effect is small but still detectable at school age.

The susceptibility of the rodent mammary gland to known chemical carcinogens can vary with the stage of gland development. Full-term pregnancy (parity) can confer permanent structural and functional changes in the gland that are associated with decreased breast cancer risk in humans and protection from mammary carcinogenesis in rodents. In this study, the formation and persistence of benzo[a]pyrene (B[a]P)-derived DNA adducts in vivo was determined in the abdominal mammary organs of adult nulliparous and parous BALB/c mice treated orally with the carcinogen. Mammary DNA isolated from animals in both groups revealed only one major adduct on TLC maps by P1-nuclease 32P-postlabeling analysis. The major adduct co-migrated with the (+)-enantiomer of anti-BPDE-dGp. Much lower levels of the (-)-enantiomer were detected. Most of the adduct quantitated was probably contributed by cells of the stromal compartment, since the gland-free organ (cleared fat pad) generated essentially equivalent profiles and level of adduct by 32P-postlabeling. Comparable levels of the B[a]P-derived adduct were observed in the intact mammary organ of both nulliparous and parous mice during a time course from 1 to 28 days after treatment. In both cases, adduct removal occurred exponentially with a half-life of approximately 16 days. The capacity for de novo formation of reactive metabolites by the mammary organ was demonstrated in vitro: digests of DNA from mammary mince exposed to B[a]P generated an adduct on TLC maps that also co-migrated with the (+)-anti-BPDE-dGp standard. Thus, our cumulative findings confirm the capacity of mammary cells to form potentially carcinogenic DNA adducts; however, the functional changes that occur in the mouse mammary gland as a result of parity did not influence the profile, level or persistence of adduct following exposure to a known carcinogen. Other factors, such as changes in mammary cell cycle kinetics or responsiveness to promotional stimuli may be more causally related to reduction in incidence of neoplasia observed in parous animals.

Identification of tumor suppressor gene loci in rodent cell culture systems has relied upon the use of somatic cell hybridization studies. Although normal rodent fibroblasts are capable of suppressing the tumorigenicity of a variety of tumor cells, the lack of complementation in tumor cell x tumor cell hybrids has left the possibility that a single tumor suppressor gene may be responsible for tumor suppression in a particular rodent cell culture system. Using this same approach, we found no evidence for complementation resulting in suppression of the transformed phenotype when three viral oncogene-transformed Syrian hamster embryo (SHE) cell lines and one spontaneously transformed baby hamster kidney (BHK) cell line were fused to benzo[a]pyrene-transformed SHE cells (BP6T-M3). However, v-src oncogene-transformed cell line (srcT) x BP6T-M3 hybrids did demonstrate limited suppression of the transformed phenotype, suggesting at least two complementing tumor suppressor genes in this system. We were able to confirm and extend this finding using another experimental approach with preneoplastic hamster cell lines that are immortal in culture but nontumorigenic in nude mice. We propose that fusion of these preneoplastic cells to various tumor cells may reveal tumor suppressor genes not evident in the tumor cell x tumor cell complementation studies. Subclones of two nontumorigenic, immortal hamster cell lines, 10W and DES4, displayed differing abilities to suppress BP6T-M3 cells in somatic cell hybrids, as quantitated by the ability of the hybrid cells to form colonies in soft agar. With a panel of preneoplastic hamster cell x BP6T-M3 hybrids, a distinct pattern of suppression or expression of the transformed phenotype was observed. Marked differences in this pattern were seen when the same 10W and DES4 subclones were fused to other hamster fibrosarcoma cell lines, indicating different tumor suppressing activities of multiple tumor suppressor genes. Analysis of this data suggests that as few as three or as many as six different tumor suppressor genes may be active in the Syrian hamster embryo cell culture system. Thus, this system may provide a useful model for identifying and studying the effects and regulation of a number of different tumor suppressor genes for fibrosarcomas.

Polychlorinated biphenyls (PCBs) are a family of 209 chemicals with two linked phenyl rings and variable chlorination. They are clear oils at room temperature. They were produced from the 1930s until banned in the 1970s because of toxicity and evidence of widespread environmental contamination. They were used mostly as insulators in electrical equipment; their widespread occurrence in the environment is more a consequence of uncontrolled disposal than of deliberate dissemination. In Asia, there have been two outbreaks of poisoning due to cooking oil contaminated by thermally degraded PCBs. Studies in workers exposed chronically to "clean" PCBs, workers exposed acutely to thermally degraded PCBs in clean-up of fires, and adult patients in Asia who ingested contaminated rice oil consistently show slowed nerve conduction and sometimes show headache, lassitude, and other CNS symptoms. In children exposed to background levels in the US, those with the highest transplacental exposure show hypotonia and hyporeflexia at birth and slowed motor development through age two, a defect in visual memory processing at 7 mon, and defects in short term memory at 4 years. Despite the presence of PCBs in breast milk, no association between breast milk exposure and any measured outcome has been seen other than lower activity levels at 4 years among long term breast fed children at the highest PCB levels. In Asia, children who were in utero at or after the 1968 exposure in Japan or the 1979 exposure in Taiwan showed clinically evident developmental delay. In Taiwan, the children were shown to have a variety of ectodermal defects, but the association between these defects and developmental delay was weak.(ABSTRACT TRUNCATED AT 250 WORDS)

Animal data suggest that prenatal exposure to certain tobacco smoke components such as nicotine may affect the development of the male gonadal axis, which may in turn affect future adult fertility. There are no previous epidemiologic studies on the potential effects of early (prenatal and childhood) exposure to maternal smoking on the reproductive system in adult male offspring. To investigate this question, we used data from a follow-up study of reproductive function and fertility among young adult sons of mothers who had participated in a randomized clinical trial of diethylstilbestrol use during pregnancy. We observed no significant effects of early exposure to maternal smoking on conventional semen characteristics, hormone levels (follicle stimulating hormone [FSH], luteinizing hormone [LH] and testosterone), urogenital abnormalities and diseases, or perceived infertility problems. Current active smoking by the men was, however, associated with a significant decrease in the percentage of sperm with normal morphology.