Identifying critical windows of exposure for children's health.

Several authors have considered the importance of exposure timing and how this affects the outcomes observed, but no one has systematically compiled preconceptional, prenatal, and postnatal developmental exposures and subsequent outcomes. Efforts were undertaken to examine the information available and to evaluate implications for risk assessment for several areas: a) respiratory and immune systems, b) reproductive system, c) nervous system, d) cardiovascular system, endocrine system, and general growth, and e) cancer. Major conclusions from a workshop on "Critical Windows of Exposure for Children's Health" included a) broad windows of sensitivity can be identified for many systems but detailed information is limited; b) cross-species comparisons of dose to target tissue and better data on the exposure-dose-outcome continuum are needed; c) increased interaction among scientific disciplines can further understanding by using laboratory animal results in designing epidemiological studies and human data to suggest specific laboratory studies on mechanisms and agent-target interactions; and d) thus far, only limited attention has been given to peripubertal/adolescent exposures, adult consequences of developmental exposures, and genome-environment interactions. More specific information on developmental windows will improve risk assessment by identifying the most sensitive window(s) for evaluation of dose-response relationships and exposure, evaluation of biological plausibility of research findings in humans, and comparison of data across species. In public health and risk management, information on critical windows may help identify especially susceptible subgroups for specific interventions.

Fetal growth and maternal exposure to particulate matter during pregnancy.

Prior studies reported an association between ambient air concentrations of total suspended particles and SO2 during pregnancy and adverse pregnancy outcomes. We examined the possible impact of particulate matter up to 10 microm (PM10) and up to 2.5 microm (PM2. 5) in size on intrauterine growth retardation (IUGR) risk in a highly polluted area of Northern Bohemia (Teplice District). The study group includes all singleton full-term births of European origin over a 2-year period in the Teplice District. Information on reproductive history, health, and lifestyle was obtained from maternal questionnaires. The mean concentrations of pollutants for each month of gestation were calculated using continuous monitoring data. Three intervals (low, medium, and high) were constructed for each pollutant (tertiles). Odds ratios (ORs) for IUGR for PM10 and PM2.5 levels were generated using logistic regression for each month of gestation after adjustment for potential confounding factors. Adjusted ORs for IUGR related to ambient PM10 levels in the first gestational month increased along the concentration intervals: medium 1.62 [95% confidence interval (CI), 1.07-2.46], high 2.64 (CI, 1.48-4.71). ORs for PM2.5 were 1.26 (CI, 0.81-1.95) and 2.11 (CI, 1. 20-3.70), respectively. No other associations of IUGR risk with particulate matter were found. Influence of particles or other associated air pollutants on fetal growth in early gestation is one of several possible explanations of these results. Timing of this effect is compatible with a current hypothesis of IUGR pathogenesis. Seasonal factors, one of the other possible explanations, is less probable. More investigation is required to examine these findings and alternative explanations.

Semen quality and reproductive health of young Czech men exposed to seasonal air pollution.

This study of male reproductive health in the Czech Republic resulted from community concern about potential adverse effects of air pollution. We compared young men (18 years of age) living in Teplice, a highly industrialized district with seasonally elevated levels of air pollution, to those from Prachatice, a rural district with relatively clean air. Surveys were scheduled for either late winter, after the season of higher air pollution, or at the end of summer, when pollution was low. Participation included a physical examination, donation of a semen sample, and completion of a questionnaire on health, personal habits, and exposure to solvents and metals through work or hobby. Analysis of data from 408 volunteers showed that the men from Teplice and Prachatice were similar in physical characteristics, personal habits, and work- or hobby-related exposures. Sixty-six percent (272) of these men donated a single semen sample for routine semen analysis, computer-aided sperm motion analysis, and sperm chromatin structure assay. The mean (median) sperm concentration and sperm count were 61. 2 (44.0) million/mL semen and 113.3 (81.5) million, respectively, and were not associated with district of residence or period of elevated air pollution. However, periods of elevated air pollution in Teplice were significantly associated with decrements in other semen measures including proportionately fewer motile sperm, proportionately fewer sperm with normal morphology or normal head shape, and proportionately more sperm with abnormal chromatin. These results suggest that young men may experience alterations in sperm quality after exposure to periods of elevated air pollution, without changes in sperm numbers.

Overview of a workshop on quantitative models for developmental toxicity risk assessment.

A workshop was held to discuss potential advancements to improve the precision of risk estimates for developmental toxicity. This paper presents an overview of the discussions at the workshop, focusing on the risk assessment process and science policy considerations important in the use of quantitative models. Some of the pertinent biological considerations are reviewed, particularly those related to the repair capacity of the developing organism and how this affects the concept of a threshold for developmental toxicity effects, as well as the maternal and litter influences on developmental toxicity outcomes. Finally, the current status of use of quantitative approaches is described, possible short-term approaches are discussed, and future research needs in this area are outlined.

Teplice program--the impact of air pollution on human health.

The aim of the Teplice Program is to investigate and assess the impact of air pollution on the health of the population in the district of Teplice, Czech Republic. Characterization of the air pollutants demonstrated unusually high concentrations during winter inversions of fine particles dominated by acidic sulfates, genotoxic organic compounds, and toxic trace elements. The major source of airborne fine particles is the burning of coal for heating and power. Human exposure and biomarker studies demonstrated large seasonal variations in air pollution within the Teplice District and higher seasonal average pollution levels than the comparative district, Prachatice. Personal exposures to fine particles and organic carcinogens [e.g., polycyclic aromatic hydrocarbons (PAH)] were correlated with excretion of PAH metabolites in urine, several trace metals in blood, and DNA adducts in white blood cells. Respiratory and neurobehavioral studies of school children were conducted using questionnaires and clinical measures. A significantly higher prevalence of adverse respiratory symptoms and decreased lung function were found in the Teplice district than in Prachatice. The neurobehavioral studies indicated significantly higher teacher referrals for clinical assessment in Teplice, but the majority of objective performance measures did not differ. Reproductive studies were conducted in both males and females. A study of the effects of exposure on pregnancy and birth found an excess prevalence of low birth weight and premature births in Teplice; these adverse effects were more common in infants conceived in the winter and whose mothers were smokers. Based on questionnaires and medical examination, the reproductive development of young men was not different between districts and seasons, however, measures of semen quality suggest that exposure to high levels of air pollution are associated with transient decrements in semen quality.

Estimates of human fertility and pregnancy loss.

OBJECTIVE: To examine the fertility and pregnancy wastage rates in a group of presumably fertile couples. DESIGN: Prospective observational study of 200 couples desiring to achieve pregnancy over 12 menstrual cycles coupled with pregnancy outcome follow-up. SETTING: A university-based obstetrics and gynecological center. PATIENTS: Personal interviews and questionnaires were used to screen couples for entry into the study. Couples were counseled to have intercourse centered on predicted day of ovulation. Phase 1 included the first three cycles in which women collected daily morning urine samples, underwent midcycle postcoital tests, and, if late for their menses, presented for serum hCG testing. Phase 2 encompassed the next nine cycles in which women were contacted monthly by phone and underwent serum hCG testing if menses was delayed. Urine samples from cycles in which clinical (serum hCG) pregnancy did not occur underwent sensitive hCG testing to detect occult pregnancies. Pregnancies were followed until delivery to ascertain outcome. RESULTS: Eighty-two percent of the 200 couples followed for the entire study period conceived. The maximal fertility rate was approximately 30% per cycle in the first two cycles. This rate quickly tapered over the remainder of the study. Pregnancy wastage during phase 1 accounted for 31% of the pregnancies detected. Forty-one percent (15/36) of these losses were seen only by urine hCG testing and were categorized as occult. Eleven of these same patients later achieved clinically recognized conceptions during the study. CONCLUSIONS: These results support the concept that the efficiency of human reproduction is maximum at approximately 30% per cycle. A very significant number of these pregnancies end in spontaneous abortion. In addition, pregnancy loss before missed menses occurs in a significant proportion of women.

Smoking cigarettes is associated with increased sperm disomy in teenage men.

OBJECTIVE: To determine whether moderate cigarette smoking and alcohol consumption in teenage men is associated with increases in disomic sperm and detectable changes in semen quality. DESIGN: Cohort study. SETTING: Military recruiting station, Teplice, Czech Republic. PATIENT(S): Ten current smokers (20 cigarettes per day for at least 2 years, exposure confirmed by urine cotinine) who also consumed alcohol and 15 nonsmokers. All patients were exactly 18 years old, healthy, and of unproven fertility. MAIN OUTCOME MEASURE(S): Sperm aneuploidy by multicolor fluorescence in situ hybridization for chromosomes 8, X, and Y; conventional semen analyses; computer-aided sperm analysis for motility; and sperm chromatin structure analysis. RESULTS: Smokers showed elevated frequencies of sperm aneuploidy (Y disomy, P <0.001; aggregate of X, Y, and 8 disomies, P <0.01); reduced linearity of sperm motion (P <0.05); and more "round-headed" sperm (P <0.01). Smokers' semen contained fewer sperm (P <0.001) and fewer motile sperm (P <0.02), which was attributable, in part, to shorter abstinence intervals among smokers (P <0.02). CONCLUSION(S): Cigarette smoking among teenagers was associated with increases in disomic sperm and a diminution in specific aspects of semen quality. Such defects may affect male fertility and may increase future chances of fathering offspring with aneuploidy syndromes.

Semen quality and human fertility: a prospective study with healthy couples.

Measures of semen quality are used as surrogate measures of male fertility in clinical andrology, reproductive toxicology, epidemiology, and risk assessment. However, only limited data are available to relate those measures to fertility. This prospective study with 210 reproductive-age couples was conducted to provide information on the value of semen quality measures for predicting human male fertility potential and for development of models to estimate the effects of changes in semen quality on fertility in a given population for risk assessment. Couples without known risk factors for infertility and who had discontinued contraception to have a child were accepted. The study followed each couple for up to 12 menstrual cycles while they attempted to conceive and evaluated semen quality measures from multiple ejaculates per man with known abstinence intervals. For each cycle, the day of ovulation was predicted, and the couple was advised to have intercourse multiple times on that day and on the days around it. Among the demographic variables assessed, parity, contraception status prior to entering the study, male education level, and male smoking were associated significantly with 12-cycle pregnancy rate. Several semen quality measures also were associated significantly with pregnancy rate, with percentage morphologically normal sperm by strict criteria and measures involving total number of sperm showing particularly strong associations. Localized regression-smoothing plots of semen quality data against proportion of couples pregnant suggested levels below which fertility declines for several semen quality measures. These results have applications in both clinical andrology and in assessment of risk to male fecundity from environmental or pharmaceutical exposures. In particular, they contribute information on behavior of fertility with varying semen quality and can allow development of models to predict effects on fertility in populations from decrements in semen quality.

Evaluation of a container for collection and shipment of semen with potential uses in population-based, clinical, and occupational settings.

Large, population-based studies of semen quality are encumbered by the logistics and expense of obtaining semen samples from men who live in a variety of locations. A prototype semen collection and transportation kit, the TRANSEM100, can be distributed to study participants and then directly shipped to a central laboratory for analysis. This study was designed to evaluate the ability of male volunteers to correctly use the kit. Thirty volunteers aged 20 to 44 years with no history of diabetes, recent chemotherapy, fertility problems, or vasectomy were recruited through a newspaper advertisement, interviewed to obtain demographic information, and instructed on the use of the kit. Twenty-six of the initial subjects provided at least 1 semen specimen using the kit and returned the specimens by overnight delivery to the laboratory for analysis, 25 completed a follow-up interview on the use of the collection kit, and 20 submitted a second semen sample using the same method. The average volunteer was white, 27.8 years old, and held at least a college degree. Forty percent of the volunteers were married. In general, participants correctly followed the instructions for collecting, packaging, and shipping the semen samples. Volunteers were instructed to collect samples after at least 2, but no more than 7 days of abstinence. For the first and second samples submitted, participants collected semen samples after an average of 3.3 and 3.9 days of abstinence, respectively. Seventeen (65%) of the samples from the first sampling period and 16 (80%) of the samples from the second period were received in the laboratory the day after they had been collected. In summary, the TRANSEM100 may prove to be useful for collecting human semen in field studies. Further testing of this method is warranted to evaluate preservation of sample quality and use of the kit by men among diverse socioeconomic groups.

Male reproductive effects of solvent and fuel exposure during aircraft maintenance.

Few studies have addressed the effects of mixed, low-level exposures to complex mixtures on a man's reproductive potential. In this prospective study, each subject was evaluated before first exposure and at 15 and 30 weeks after exposures had begun. A total of 50 men working on aircraft maintenance at an Air Force installation were included in the study. In addition, eight unexposed men were concurrently sampled. Industrial hygiene (IH) sampling and expired breath samples were collected for jet fuel as measured by total napthas, benzene--a component of jet fuel, 1,1,1-trichloroethane, methyl ethyl ketone, xylenes, toluene, and methylene chloride. Sperm production, structure, and function (sperm concentration, sperm motion, viability, morphology, morphometrics, and stability of sperm chromatin) were evaluated. Exposures were low. All mean IH measures were below 6 ppm, which is less than 10% of the Occupational Safety and Health Administration standard for all chemicals except benzene. Sheet metal workers had the highest mean breath levels for both total solvents (24 ppb) and fuels (28.3 ppb). For most sperm measures, mean values remained in the normal range throughout the 30 weeks of exposure. When jobs were analyzed by exposure groups, some adverse changes were observed. The paint shop group had a significant decline in motility of 19.5% at 30 weeks. Internal dose measures, however, did not show a significant association with spermatogenic changes.

An inventory of human exposure-related data bases.

An inventory of Federally-sponsored data bases, which either have been or could be used to estimate human exposures to environmental agents, was compiled through a joint effort by the Environmental Protection Agency (EPA), the National Center for Health Statistics (CDC-NCHS), and the Agency for Toxic Substances and Disease Registry (ATSDR). The inventory includes sixty-seven exposure-related data systems that meet the following criteria: cover a relatively large geographical area (e.g., national, state); provide reasonable access to information; and are supported, at least in part, by Federal funds. Findings allow for comparison of data bases according to 1) exposure estimators (e.g., emission estimates, environmental measurements), 2) sample types (e.g., air, water soil, food, human tissue), 3) measured/observed parameters (e.g., pesticides, PCBs, microorganisms), 4) geographic scope (e.g., national, regional, state), 5) sample collection frequency (e.g., yearly, quarterly, daily), and 6) sample location identifiers (e.g., latitude/longitude, zip code, county). Results indicate that existing data bases were established for a variety of reasons (e.g., regulatory compliance, research, monitor environmental conditions, legal requirements) and contain information which varies widely in terms of quality, relevance, and availability. Although the inventory identifies many potential sources of information, it also highlights significant shortcomings in the available systems, including an almost complete absence of data on contact between people and environmental agents (human exposure) and on the amount of the agent that is absorbed into the body (dose).

Design considerations in pregnancy outcome studies of occupational populations.

Increased attention has been focused on the relationship between adverse pregnancy outcomes and occupational exposures to parents of both sexes. However, the characteristics and dynamics of working populations impose limitations on potential study populations. These limitations result from the combined effects of workforce size, exposure, age distribution, and marital status, which limit the number of pregnancies available for study. The smaller populations available typically result in retrospective studies covering extended time periods. Potential data sources for these studies include interview data, medical records, vital statistics data, and insurance records. All sources may have biased ascertainment of certain pregnancy outcomes such as early fetal loss due to errors in recall in interview data, legal requirements for recording vital statistics data, and differences in medical care patterns.

Use of exposure data in occupational reproductive studies.

Accurately characterizing worker exposure presents some unique problems in occupational reproductive studies. The latency period between exposure and the adverse event may be relatively brief - days, weeks, or months. Inaccurately identifying the specific exposure period which initiated the adverse event may then contribute to sizeable misclassification errors. This paper discusses different types of exposure models that can be used to help reduce misclassification and delineate the exposure-effect relationships more accurately. The advantages and disadvantages of exposure data sources are also discussed.

Estimating human exposures to environmental pollutants: availability and utility of existing databases.

Information about human exposures to environmental agents is a crucial component of informed decisions about protection of public health. Results from an inventory of exposure-related databases are used to examine the value of exposure information for risk assessment, risk management, surveillance of status and trends, and epidemiologic studies. Findings indicate that current and future exposure-related databases should include (1) standardized procedures for the collection, storage, analysis, and reporting of data; (2) an enhanced ability to compare data over time, i.e., conduct comparison studies of "old" and "new" methods; (3) mechanisms for coordination and cooperation among public and private-sector organizations with respect to the design, maintenance, exchange, and review of information systems; (4) measurements of actual exposures and dose for relevant human populations; and (5) data collection, storage, and retrieval methods that permit easy manipulation of information for both model building and testing.

Role of exposure databases in epidemiology.

At present, exposure databases record data primarily for regulatory purposes; they have not focused on serving the needs of epidemiologists or public health. However, the modification of exposure databases could facilitate their use in epidemiology. Characteristics necessary to enhance the use of all databases include easy access by users; documentation of methods, sampling bias, error, and inconsistences; widespread coverage in time and space; and methods and measures for estimating exposure of individuals as well as populations. Also needed are exposure scenarios and models to estimate exposures for geographic areas and time intervals not currently sampled. Multidisciplinary teams are needed to examine current databases, to review strategies for improving data collection, and to suggest and help implement appropriate changes. A long-term goal is to develop and validate data from exposure scenarios and models using data on the relationship of exposure to doses measured in humans.

[The environment, life style and pregnancy outcome]. / Zivotní prostredí, zivotní styl a výsledky tehotenství.

BACKGROUND: Unproved statement is frequently suggested, that pregnancy outcome in mining districts of Northern Bohemia is damaged due to high level of pollution. The aim of study is to compare the pregnancy outcome of women from the mining district of Teplice (with extremely high air pollution) with that of Prachatice (district with relatively low pollution level) and to evaluate the relative impact of various factors (environmental exposure, lifestyle variables, individual exposures). In the preliminary communication the study design is described and first results are discussed. METHODS AND RESULTS: About 2260 pregnancies terminated by delivery in Teplice and Prachatice districts from April 1994 till June 1995 were enrolled. In the prospective cohort study all pregnancies terminated during 1994-1997 will be included. Data about reproduction and health history and lifestyle are obtained from questionnaires completed by mothers and medical staff. As indicators of reproductive damage low birth weight (< 2500 g) and premature birth (< 37th week) are used. Preliminary descriptive results obtained during first 14 months of data collection are discussed. Prevalence of low birth weight was 8.8% in the district of Teplice but only 4.0% in Prachatice (P < 0.001). It is 6.2% and 3.4% for prematurity (P < 0.01). However, 14.1% Gypsy births were found in Teplice whereas only 2.9% in Prachatice (P < 0.001). Prevalence of low birth weight is 23.6% and that of prematurity 13.4% among Gypsy births. Significant linear relationship of low birth weight (P < 0.0001) and prematurity (P < 0.0001) with number of cigarettes smoked by mother at early pregnancy was found. Significantly higher proportion of Teplice mothers smokes significantly more cigarettes (P < 0.0001). Relative risk of premature birth of infants conceived in winter by smoking mothers is 3.2 times higher for non-Gypsies (P < 0.0001) and 6.5 times higher by Gypsies (P < 0.0001). CONCLUSIONS: Differences of prevalence of low birth weights and prematurity between Teplice and Prachatice districts would be explained partly by differences in ethnic structure and smoking habits. However, the difference remains significant statistically just after exclusion of both factors mentioned. The adverse effect of the Winter conception period on the prematurity prevalence could be due to synergistic effect of smoking and environmental load (increased level of pollutants in winter period); simultaneous action of both factors may exceed the threshold of protective mechanisms.

[Maternal exposure to dust particles during pregnancy and fetal growth in 2 regions with different levels of air pollution]. / Expozice matky prachovým cásticím tehotenství a rust plodu ve dvou regionech s rozdílnou úrovní znecisteného ovzdusí.

BACKGROUND: Recently, an association between adverse pregnancy outcome and air pollution was hypothesized in several papers. The aim of the present study is to evaluate the impact of particles with aerodynamic diameter < or = 10 microns (PM10) on the intrauterine growth retardation (IUGR) in two regions with the different levels of air pollution. METHODS AND RESULTS: The study group includes all singleton full term births of European origin over a two-year period in the district of Teplice (n = 1,943) and Prachatice (n = 883). Information on reproductive and health history and lifestyle was obtained from maternal questionnaires and medical records. IUGR was chosen as the indicator of reproductive effects. The mean concentration of PM10 for each women in particular gestational month was calculated. Three concentration intervals were constructed (low < 40 micrograms/m3; medium 40-50 micrograms/m3; high > or = 50 micrograms/m3). Relative risk of IUGR was estimated for particular month and pollutant level. Influence of the potential confounders (maternal age, height and pre-pregnancy weight, smoking, season and the year of study) was controlled using logistic regression models; adjusted odd's ratio (AOR) was estimated. Relative risk of IUGR in Teplice District was increased for medium PM10 levels (AOR = 1.62 CI: 1.07-2.46) (P < 0.02) as well as for high levels in the first gestational month (2.64 CI: 1.48-4.71) (P < 0.001). The same association was observed also in Prachatice District, though the PM10 did not achieve the "high" levels (> or = 50 micrograms/m3). AOR for IUGR for mothers exposed in the 1st gestational month to medium PM10 levels was three times the risk of those exposed to low levels (3.50 CI: 1.82-6.81) (P < 0.0003). No similar relationship was observed in any other gestational stage. CONCLUSIONS: Influence of particles or other associated air pollutants on fetal growth in early gestation is one of several possible explanations of these results. Timing of this effect in both different regions is compatible with a current hypothesis of IUGR etio-pathogenesis. Seasonal factors, one of the other possible explanations, is less probable. More investigation is required to evaluate a possible causal nature of the relationship observed.

Pesticide concentrations in Arkansas breast milk.

During an episode of pesticide dairy product contamination in Arkansas in 1986, breast milk samples from 942 women were analyzed for concentrations of chlorinated pesticides. The pesticides found most frequently in quantifiable concentrations were p,p'-DDE (100%), oxychlordane (84%), trans-nonachlor (77%), heptachlor epoxide (74%) and beta-HCH, an isomer of lindane (27%). The pesticides present in highest mean concentrations of all samples analyzed (reported as ppm in milk fat) were p,p'-DDE (0.952 ppm), trans-nonachlor (0.062 ppm), oxychlordane (0.051 ppm), heptachlor epoxide (0.045 ppm), p,p'-DDT (0.039 ppm), and beta-HCH (0.032 ppm). These concentrations are lower than previous reports from similar regions of the US. However, continued persistence in human breast milk is of concern due to potential adverse health effects from these chemicals.

The dose-response fallacy in human reproductive studies of toxic exposures.

The manner in which exposure is defined can affect the findings of reproductive studies of toxic exposures. The individual end points potentially examined, such as fetal loss, subfertility, and congenital malformations observed at birth, are on a continuum by severity of effect: The most extreme effect of the three being infertility because no pregnancy is possible, and the least extreme, congenital malformations recognized at birth. End points observed at birth are survivors of a long and complex process. The process yielding one of these adverse end points may result from a number of factors, including level of exposure. For example, a very high exposure could result in early fetal loss, whereas a lower one might result in a congenital malformation observed at birth. If the probability of a less severe end point falls due to increasing probability of more severe end points with increasing exposure, then a nontraditional dose-response relationship may be observed in the study of one type of outcome.