Showing papers in "Environmental Health Perspectives in 2000"

Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models.

Abstract: Vulnerable periods during the development of the nervous system are sensitive to environmental insults because they are dependent on the temporal and regional emergence of critical developmental processes (i.e., proliferation, migration, differentiation, synaptogenesis, myelination, and apoptosis). Evidence from numerous sources demonstrates that neural development extends from the embryonic period through adolescence. In general, the sequence of events is comparable among species, although the time scales are considerably different. Developmental exposure of animals or humans to numerous agents (e.g., X-ray irradiation, methylazoxymethanol, ethanol, lead, methyl mercury, or chlorpyrifos) demonstrates that interference with one or more of these developmental processes can lead to developmental neurotoxicity. Different behavioral domains (e.g., sensory, motor, and various cognitive functions) are subserved by different brain areas. Although there are important differences between the rodent and human brain, analogous structures can be identified. Moreover, the ontogeny of specific behaviors can be used to draw inferences regarding the maturation of specific brain structures or neural circuits in rodents and primates, including humans. Furthermore, various clinical disorders in humans (e.g., schizophrenia, dyslexia, epilepsy, and autism) may also be the result of interference with normal ontogeny of developmental processes in the nervous system. Of critical concern is the possibility that developmental exposure to neurotoxicants may result in an acceleration of age-related decline in function. This concern is compounded by the fact that developmental neurotoxicity that results in small effects can have a profound societal impact when amortized across the entire population and across the life span of humans.

Association of fine particulate matter from different sources with daily mortality in six U.S. cities.

Abstract: Previously we reported that fine particle mass (particulate matter [less than and equal to] 2.5 microm; PM(2.5)), which is primarily from combustion sources, but not coarse particle mass, which is primarily from crustal sources, was associated with daily mortality in six eastern U.S. cities (1). In this study, we used the elemental composition of size-fractionated particles to identify several distinct source-related fractions of fine particles and examined the association of these fractions with daily mortality in each of the six cities. Using specific rotation factor analysis for each city, we identified a silicon factor classified as soil and crustal material, a lead factor classified as motor vehicle exhaust, a selenium factor representing coal combustion, and up to two additional factors. We extracted daily counts of deaths from National Center for Health Statistics records and estimated city-specific associations of mortality with each source factor by Poisson regression, adjusting for time trends, weather, and the other source factors. Combined effect estimates were calculated as the inverse variance weighted mean of the city-specific estimates. In the combined analysis, a 10 microg/m(3) increase in PM(2.5) from mobile sources accounted for a 3.4% increase in daily mortality [95% confidence interval (CI), 1.7-5.2%], and the equivalent increase in fine particles from coal combustion sources accounted for a 1.1% increase [CI, 0.3-2.0%). PM(2.5) crustal particles were not associated with daily mortality. These results indicate that combustion particles in the fine fraction from mobile and coal combustion sources, but not fine crustal particles, are associated with increased mortality.

Exposure measurement error in time-series studies of air pollution: concepts and consequences.

Abstract: Misclassification of exposure is a well-recognized inherent limitation of epidemiologic studies of disease and the environment. For many agents of interest, exposures take place over time and in multiple locations; accurately estimating the relevant exposures for an individual participant in epidemiologic studies is often daunting, particularly within the limits set by feasibility, participant burden, and cost. Researchers have taken steps to deal with the consequences of measurement error by limiting the degree of error through a study's design, estimating the degree of error using a nested validation study, and by adjusting for measurement error in statistical analyses. In this paper, we address measurement error in observational studies of air pollution and health. Because measurement error may have substantial implications for interpreting epidemiologic studies on air pollution, particularly the time-series analyses, we developed a systematic conceptual formulation of the problem of measurement error in epidemiologic studies of air pollution and then considered the consequences within this formulation. When possible, we used available relevant data to make simple estimates of measurement error effects. This paper provides an overview of measurement errors in linear regression, distinguishing two extremes of a continuum-Berkson from classical type errors, and the univariate from the multivariate predictor case. We then propose one conceptual framework for the evaluation of measurement errors in the log-linear regression used for time-series studies of particulate air pollution and mortality and identify three main components of error. We present new simple analyses of data on exposures of particulate matter < 10 microm in aerodynamic diameter from the Particle Total Exposure Assessment Methodology Study. Finally, we summarize open questions regarding measurement error and suggest the kind of additional data necessary to address them.

Noise exposure and public health.

Abstract: Exposure to noise constitutes a health risk. There is sufficient scientific evidence that noise exposure can induce hearing impairment, hypertension and ischemic heart disease, annoyance, sleep disturbance, and decreased school performance. For other effects such as changes in the immune system and birth defects, the evidence is limited. Most public health impacts of noise were already identified in the 1960s and noise abatement is less of a scientific but primarily a policy problem. A subject for further research is the elucidation of the mechanisms underlying noise-induced cardiovascular disorders and the relationship of noise with annoyance and nonacoustical factors modifying health outcomes. A high priority study subject is the effects of noise on children, including cognitive effects and their reversibility. Noise exposure is on the increase, especially in the general living environment, both in industrialized nations and in developing world regions. This implies that in the twenty-first century noise exposure will still be a major public health problem.

Epidemiology of fine particulate air pollution and human health: biologic mechanisms and who's at risk?

Abstract: This article briefly summarizes the epidemiology of the health effects of fine particulate air pollution, provides an early, somewhat speculative, discussion of the contribution of epidemiology to evaluating biologic mechanisms, and evaluates who's at risk or is susceptible to adverse health effects. Based on preliminary epidemiologic evidence, it is speculated that a systemic response to fine particle-induced pulmonary inflammation, including cytokine release and altered cardiac autonomic function, may be part of the pathophysiologic mechanisms or pathways linking particulate pollution with cardiopulmonary disease. The elderly, infants, and persons with chronic cardiopulmonary disease, influenza, or asthma are most susceptible to mortality and serious morbidity effects from short-term acutely elevated exposures. Others are susceptible to less serious health effects such as transient increases in respiratory symptoms, decreased lung function, or other physiologic changes. Chronic exposure studies suggest relatively broad susceptibility to cumulative effects of long-term repeated exposure to fine particulate pollution, resulting in substantive estimates of population average loss of life expectancy in highly polluted environments. Additional knowledge is needed about the specific pollutants or mix of pollutants responsible for the adverse health effects and the biologic mechanisms involved.

Marine algal toxins: origins, health effects, and their increased occurrence.

Abstract: Certain marine algae produce potent toxins that impact human health through the consumption of contaminated shellfish and finfish and through water or aerosol exposure. Over the past three decades, the frequency and global distribution of toxic algal incidents appear to have increased, and human intoxications from novel algal sources have occurred. This increase is of particular concern, since it parallels recent evidence of large-scale ecologic disturbances that coincide with trends in global warming. The extent to which human activities have contributed to their increase therefore comes into question. This review summarizes the origins and health effects of marine algal toxins, as well as changes in their current global distribution, and examines possible causes for the recent increase in their occurrence.

Groundwater arsenic contamination in Bangladesh and West Bengal, India.

Abstract: Nine districts in West Bengal, India, and 42 districts in Bangladesh have arsenic levels in groundwater above the World Health Organization maximum permissible limit of 50 microg/L. The area and po...

The question of declining sperm density revisited: an analysis of 101 studies published 1934-1996.

Abstract: In 1992 Carlsen et al. reported a significant global decline in sperm density between 1938 and 1990 [Evidence for Decreasing Quality of Semen during Last 50 Years. Br Med J 305:609-613 (1992)]. We subsequently published a reanalysis of the studies included by Carlsen et al. [Swan et al. Have Sperm Densities Declined? A Reanalysis of Global Trend Data. Environ Health Perspect 105:1228-1232 (1997)]. In that analysis we found significant declines in sperm density in the United States and Europe/Australia after controlling for abstinence time, age, percent of men with proven fertility, and specimen collection method. The declines in sperm density in the United States (approximately 1.5%/year) and Europe/Australia (approximately 3%/year) were somewhat greater than the average decline reported by Carlsen et al. (approximately 1%/year). However, we found no decline in sperm density in non-Western countries, for which data were very limited. In the current study, we used similar methods to analyze an expanded set of studies. We added 47 English language studies published in 1934-1996 to those we had analyzed previously. The average decline in sperm count was virtually unchanged from that reported previously by Carlsen et al. (slope = -0.94 vs. -0.93). The slopes in the three geographic groupings were also similar to those we reported earlier. In North America, the slope was somewhat less than the slope we had found for the United States (slope = -0.80; 95% confidence interval (CI), -1.37--0.24). Similarly, the decline in Europe (slope = -2.35; CI, -3.66--1.05) was somewhat less than reported previously. As before, studies from other countries showed no trend (slope = -0.21; CI, -2.30-1.88). These results are consistent with those of Carlsen et al. and our previous results, suggesting that the reported trends are not dependent on the particular studies included by Carlsen et al. and that the observed trends previously reported for 1938-1990 are also seen in data from 1934-1996.

Blue babies and nitrate-contaminated well water.

Abstract: The use of nitrate-contaminated drinking water to prepare infant formula is a well-known risk factor for infant methemoglobinemia. Affected infants develop a peculiar blue-gray skin color and may become irritable or lethargic, depending on the severity of their condition. The condition can progress rapidly to cause coma and death if it is not recognized and treated appropriately. Two cases of blue baby syndrome were recently investigated. Both cases involved infants who became ill after being fed formula that was reconstituted with water from private wells. Water samples collected from these wells during the infants' illnesses contained nitrate-nitrogen concentrations of 22.9 and 27.4 mg/L.

Fetal, infant, and childhood growth are predictors of coronary heart disease, diabetes, and hypertension in adult men and women.

Abstract: Many human fetuses have to adapt to a limited supply of nutrients. In doing so they permanently change their structure and metabolism. These programmed changes may be the origins of a number of diseases in later life, including coronary heart disease, hypertension, and noninsulin- dependent diabetes. We review epidemiologic studies in which the incidence of these diseases has been related to the recorded, early growth of individuals, while considering factors in the adult lifestyle, such as obesity and socioeconomic status. We discuss possible mechanisms. For hypertension these mechanisms include placentation, maternal blood pressure, fetal undernutrition; childhood growth, activation of the renin-angiotensin system, renal structure, programming of the hypothalamic-pituitary-adrenal axis, vascular structure, and sympathetic nervous activity. For noninsulin-dependent diabetes we discuss mechanisms concerning both insulin resistance and insulin deficiency. We include a review of evidence for the programming of serum cholesterol and clotting factor concentrations. We address the timing of critical windows for coronary heart disease, reviewing studies that allow assessment of the relative importance of fetal, infant, and childhood growth. We argue for a research strategy that combines clinical, animal, and epidemiological studies.

Levels of seven urinary phthalate metabolites in a human reference population.

Abstract: Using a novel and highly selective technique, we measured monoester metabolites of seven commonly used phthalates in urine samples from a reference population of 289 adult humans. This analytical approach allowed us to directly measure the individual phthalate metabolites responsible for the animal reproductive and developmental toxicity while avoiding contamination from the ubiquitous parent compounds. The monoesters with the highest urinary levels found were monoethyl phthalate (95th percentile, 3,750 ppb, 2,610 microg/g creatinine), monobutyl phthalate (95th percentile, 294 ppb, 162 microg/g creatinine), and monobenzyl phthalate (95th percentile, 137 ppb, 92 microg/g creatinine), reflecting exposure to diethyl phthalate, dibutyl phthalate, and benzyl butyl phthalate. Women of reproductive age (20-40 years) were found to have significantly higher levels of monobutyl phthalate, a reproductive and developmental toxicant in rodents, than other age/gender groups (p < 0.005). Current scientific and regulatory attention on phthalates has focused almost exclusively on health risks from exposure to only two phthalates, di-(2-ethylhexyl) phthalate and di-isononyl phthalate. Our findings strongly suggest that health-risk assessments for phthalate exposure in humans should include diethyl, dibutyl, and benzyl butyl phthalates.

Identification of phthalate esters in the serum of young Puerto Rican girls with premature breast development.

Abstract: Premature breast development (thelarche) is the growth of mammary tissue in girls younger than 8 years of age without other manifestations of puberty. Puerto Rico has the highest known incidence of premature thelarche ever reported. In the last two decades since this serious public health anomaly has been observed, no explanation for this phenomenon has been found. Some organic pollutants, including pesticides and some plasticizers, can disrupt normal sexual development in wildlife, and many of these have been widely used in Puerto Rico. This investigation was designed to identify pollutants in the serum of Puerto Rican girls with premature thelarche. A method for blood serum analysis was optimized and validated using pesticides and phthalate esters as model compounds of endocrine-disrupting chemicals. Recovery was > 80% for all compounds. We performed final detection by gas chromatography/mass spectrometry. We analyzed 41 serum samples from thelarche patients and 35 control samples. No pesticides or their metabolite residues were detected in the serum of the study or control subjects. Significantly high levels of phthalates [dimethyl, diethyl, dibutyl, and di-(2-ethylhexyl)] and its major metabolite mono-(2-ethylhexyl) phthalate were identified in 28 (68%) samples from thelarche patients. Of the control samples analyzed, only one showed significant levels of di-isooctyl phthalate. The phthalates that we identified have been classified as endocrine disruptors. This study suggests a possible association between plasticizers with known estrogenic and antiandrogenic activity and the cause of premature breast development in a human female population.

Identifying critical windows of exposure for children's health

Abstract: 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.

Cyanobacterial toxins: removal during drinking water treatment, and human risk assessment.

Abstract: Cyanobacteria (blue-green algae) produce toxins that may present a hazard for drinking water safety. These toxins (microcystins, nodularins, saxitoxins, anatoxin-a, anatoxin-a(s), cylindrospermopsin) are structurally diverse and their effects range from liver damage, including liver cancer, to neurotoxicity. The occurrence of cyanobacteria and their toxins in water bodies used for the production of drinking water poses a technical challenge for water utility managers. With respect to their removal in water treatment procedures, of the more than 60 microcystin congeners, microcystin-LR (L, L-leucine; R, L-arginine) is the best studied cyanobacterial toxin, whereas information for the other toxins is largely lacking. In response to the growing concern about nonlethal acute and chronic effects of microcystins, the World Health Organization has recently set a new provisional guideline value for microcystin-LR of 1.0 microg/L drinking water. This will lead to further efforts by water suppliers to develop effective treatment procedures to remove these toxins. Of the water treatment procedures discussed in this review, chlorination, possibly micro-/ultrafiltration, but especially ozonation are the most effective in destroying cyanobacteria and in removing microcystins. However, these treatments may not be sufficient during bloom situations or when a high organic load is present, and toxin levels should therefore be monitored during the water treatment process. In order to perform an adequate human risk assessment of microcystin exposure via drinking water, the issue of water treatment byproducts will have to be addressed in the future.

Outdoor air pollution, low birth weight, and prematurity.

Abstract: This study tested the hypothesis, suggested by several recent reports, that air pollution may increase the risk of adverse birth outcomes. This study analyzed all singleton live births registered by the Czech national birth register in 1991 in 67 districts where at least one pollutant was monitored in 1990-1991 (n = 108,173). Maternal exposures to sulfur dioxide (SO(2)), total suspended particles (TSP), and nitrous oxides (NO(x)) in each trimester of pregnancy were estimated as the arithmetic means of all daily measurements taken by all monitors in the district of birth of each infant. Odds ratios of low birth weight (< 2,500 g), prematurity (< 37 weeks of gestation), and intrauterine growth retardation (IUGR; < 10th percentile of birth weight for gestational age and sex) were estimated by robust logistic regression. The median (and 25th and 75th percentile) trimester exposures were 32 (18, 56) microg/m(3) for SO(2); 72 (55, 87) microg/m(3) for TSP; and 38 (23, 59) microg/m(3) for NO(x). Low birth weight (prevalence 5.2%) and prematurity (prevalence 4.8%) were associated with SO(2) and somewhat less strongly with TSP. IUGR was not associated with any pollutant. The effects on low birth weight and prematurity were marginally stronger for exposures in the first trimester, and were not attenuated at all by adjustment for socioeconomic factors or the month of birth. Adjusted odds ratios of low birth weight were 1.20 [95% confidence interval (CI), 1.11-1.30] and 1.15 (CI, 1.07-1.24) for a 50 microg/m(3) increase in SO(2) and TSP, respectively, in the first trimester; adjusted odds ratios of prematurity were 1.27 (CI, 1.16-1.39) and 1.18 (CI, 1.05-1.31) for a 50 microg/m(3) increase in SO(2) and TSP, respectively, in the first trimester. Low gestational age accounted for the association between SO(2) and low birth weight. These findings provide further support for the hypothesis that air pollution can affect the outcome of pregnancy.

Semen quality and reproductive endocrine function in relation to biomarkers of lead, cadmium, zinc, and copper in men.

Abstract: Blood lead (BPb), activity of delta-aminolevulinic acid dehydratase (ALAD), erythrocyte protoporphyrin (EP), blood cadmium (BCd), serum zinc (SZn), seminal fluid zinc (SfZn), serum copper (SCu), and parameters of semen quality and of reproductive endocrine function were measured in 149 healthy male industrial workers 20-43 years of age. The group contained 98 subjects with slight to moderate occupational exposure to Pb and 51 reference subjects. All of the subjects lived in Zagreb, Croatia. Significant (p < 0.05) correlations of BPb, ALAD, and/or EP with reproductive parameters indicated a Pb-related decrease in sperm density, in counts of total, motile, and viable sperm, in the percentage and count of progressively motile sperm, in parameters of prostate secretory function (SfZn, acid phosphatase, and citric acid in seminal fluid), and an increase in abnormal sperm head morphology, serum testosterone, and estradiol. These associations were confirmed by results of multiple regression, which also showed significant (p < 0. 05) influence of BCd, SZn, SCu, smoking habits, alcohol consumption, or age on certain reproductive parameters. These effects were mainly of lower rank and intensity as compared to Pb-related reproductive effects, whereas BCd contributed to a decrease in sperm motility and an increase in abnormal sperm morphology and serum testosterone. No significant Pb- or Cd-related influence was found on levels of the lactate dehydrogenase isoenzyme LDH-C(4) and fructose in seminal fluid or on follicle-stimulating hormone, luteinizing hormone, and prolactin in serum. The seminal fluid concentrations of Pb (SfPb) and Cd (SfCd) were measured in 118 of the 149 subjects, and a highly significant (p < 0.0001) correlation was found between BPb and SfPb levels (r = 0.571) and between BCd and SfCd levels (r = 0.490). The overall study results indicate that even moderate exposures to Pb (BPb < 400 microg/L) and Cd (BCd < 10 microg/L) can significantly reduce human semen quality without conclusive evidence of impairment of male reproductive endocrine function.

The impact of polycyclic aromatic hydrocarbons and fine particles on pregnancy outcome.

Abstract: The relationship between intrauterine growth retardation (IUGR) and exposure to particulate matter [less than/equal to] 10 microm (PM(10)) and particulate matter [less than and equal to] 2.5 microm (PM(2.5))( )in early pregnancy was recently studied in the highly polluted district of Teplice (Northern Bohemia). From this observation rose the question about the possible role of the carcinogenic fraction of polycyclic aromatic hydrocarbons (c-PAHs), which are usually bound to fine particles. The impact of c-PAHs and fine particles on IUGR was analyzed in Teplice and in Prachatice, a region with similarly high c-PAH but low particle levels. All European, single live births occurring in a 4-year period in Teplice (n = 3,378) and Prachatice (n = 1,505) were included. Detailed personal data were obtained via questionnaires and medical records. Mean PM(10), PM(2.5,) and c-PAHs levels during the 9 gestational months (GM) were estimated for each mother. Adjusted odds ratios (AORs) of IUGR for three levels of c-PAHs (low, medium, and high) and for continuous data were estimated after adjustment for a range of covariates using logistic regression models. In the present 4-year sample from Teplice, previously published results about increasing IUGR risk after exposure to particles in the first GM were fully confirmed, but no such effects were found in Prachatice. The AOR of IUGR for fetuses from Teplice exposed to medium levels of c-PAHs in the first GM was 1.60 [confidence interval (CI), 1.06-2. 15], and to high levels 2.15 (CI, 27-3.63). An exposure-response relationship was established by analyzing the continuous data. For each 10 ng increase of c-PAHs in the first GM, the AOR was 1.22 (CI, 1.07-1.39). About the same relationship was observed in Prachatice in spite of the low particle levels. The results prove that exposure to c-PAHs in early gestation may influence fetal growth. The particulate matter-IUGR association observed earlier may be at least partly explained by the presence of c-PAHs on particle surfaces.

Risk of internal cancers from arsenic in drinking water.

Abstract: The U.S. Environmental Protection Agency is under a congressional mandate to revise its current standard for arsenic in drinking water. We present a risk assessment for cancers of the bladder, liver, and lung from exposure to arsenic in water, based on data from 42 villages in an arseniasis-endemic region of Taiwan. We calculate excess lifetime risk estimates for several variations of the generalized linear model and for the multistage-Weibull model. Risk estimates are sensitive to the model choice, to whether or not a comparison population is used to define the unexposed disease mortality rates, and to whether the comparison population is all of Taiwan or just the southwestern region. Some factors that may affect risk could not be evaluated quantitatively: the ecologic nature of the data, the nutritional status of the study population, and the dietary intake of arsenic. Despite all of these sources of uncertainty, however, our analysis suggests that the current standard of 50 microg/L is associated with a substantial increased risk of cancer and is not sufficiently protective of public health.

Airborne particles are a risk factor for hospital admissions for heart and lung disease.

Abstract: We examined the association between particulate matter [less than/equal to] 10 microm; (PM(10)) and hospital admission for heart and lung disease in ten U.S. cities. Our three goals were to determine whether there was an association, to estimate how the association was distributed across various lags between exposure and response, and to examine socioeconomic factors and copollutants as effect modifiers and confounders. We fit a Poisson regression model in each city to allow for city-specific differences and then combined the city-specific results. We examined potential confounding by a meta-regression of the city-specific results. Using a model that considered simultaneously the effects of PM(10) up to lags of 5 days, we found a 2.5% [95% confidence interval (CI), 1.8-3. 3] increase in chronic obstructive pulmonary disease, a 1.95% (CI, 1. 5-2.4) increase in pneumonia, and a 1.27% increase (CI, 1-1.5) in CVD for a 10 microg/m(3) increase in PM(10). We found similar effect estimates using the mean of PM(10) on the same and previous day, but lower estimates using only PM(10) for a single day. When using only days with PM(10) < 50 mg/m(3), the effect size increased by [greater/equal to] 20% for all three outcomes. These effects are not modified by poverty rates or minority status. The results were stable when controlling for confounding by sulfur dioxide, ozone, and carbon monoxide. These results are consistent with previous epidemiology and recent mechanistic studies in animals and humans.

Critical windows of exposure for children's health: cancer in human epidemiological studies and neoplasms in experimental animal models.

Abstract: In humans, cancer may be caused by genetics and environmental exposures; however, in the majority of instances the identification of the critical time window of exposure is problematic. The evidence for exposures occurring during the preconceptional period that have an association with childhood or adulthood cancers is equivocal. Agents definitely related to cancer in children, and adulthood if exposure occurs in utero, include: maternal exposure to ionizing radiation during pregnancy and childhood leukemia and certain other cancers, and maternal use of diethylstilbestrol during pregnancy and clear-cell adenocarcinoma of the vagina of their daughters. The list of environmental exposures that occur during the perinatal/postnatal period with potential to increase the risk of cancer is lengthening, but evidence available to date is inconsistent and inconclusive. In animal models, preconceptional carcinogenesis has been demonstrated for a variety of types of radiation and chemicals, with demonstrated sensitivity for all stages from fetal gonocytes to postmeiotic germ cells. Transplacental and neonatal carcinogenesis show marked ontogenetic stage specificity in some cases. Mechanistic factors include the number of cells at risk, the rate of cell division, the development of differentiated characteristics including the ability to activate and detoxify carcinogens, the presence of stem cells, and possibly others. Usefulness for human risk estimation would be strengthened by the study of these factors in more than one species, and by a focus on specific human risk issues.

Endocrine disruptors and human health--is there a problem? An update.

Abstract: It has been hypothesized that environmental exposure to synthetic estrogenic chemicals and related endocrine-active compounds may be responsible for a global decrease in sperm counts, decreased male reproductive capacity, and breast cancer in women. Results of recent studies show that there are large demographic variations in sperm counts within countries or regions, and analyses of North American data show that sperm counts have not decreased over the last 60 years. Analyses of records for hypospadias and cryptorchidism also show demographic differences in these disorders before 1985; however, since 1985 rates of hypospadias have not changed and cryptorchidism has actually declined. Temporal changes in sex ratios and fertility are minimal, whereas testicular cancer is increasing in most countries; however, in Scandinavia, the difference between high (Denmark) and low (Finland) incidence areas are not well understood and are unlikely to be correlated with differences in exposure to synthetic industrial chemicals. Results from studies on organochlorine contaminants (DDE/PCB) show that levels were not significantly different in breast cancer patients versus controls. Thus, many of the male and female reproductive tract problems linked to the endocrine-disruptor hypothesis have not increased and are not correlated with synthetic industrial contaminants. This does not exclude an endocrine-etiology for some adverse environmental effects or human problems associated with high exposures to some chemicals.

Immunologic effects of background exposure to polychlorinated biphenyls and dioxins in Dutch preschool children

Abstract: Prenatal exposure to polychlorinated biphenyls (PCBs) and dioxins is associated with changes in the T-cell lymphocyte population in healthy Dutch infants. We investigated whether these changes persist into later childhood and whether background exposure to PCBs and dioxins is associated with the prevalence of infectious or allergic diseases and humoral immunity at preschool age. The total study group consisted of 207 healthy mother-infant pairs. We estimated prenatal exposure to PCBs and dioxins by the sum of PCBs 118, 138, 153, and 180 (sigmaPCB) in maternal and cord plasma and in breast-fed infants by the dioxin, planar, and mono-ortho PCB toxic equivalent (TEQ) levels in human milk. At 42 months of age, current body burden was estimated by the PCB in plasma. We assessed the prevalence of infectious and allergic diseases by parent questionnaire, and measured humoral immunity by antibody levels for mumps, measles, and rubella after primary vaccination. We performed immunologic marker analyses of lymphocytes in a subgroup of 85 children. Prenatal PCB exposure was associated with an increased number of lymphocytes, T-cells, and CD3CD8(+) (cytotoxic), CD4(+)CD45RO(+) (memory), T-cell receptor (TcR) [alpha]ss(+), and CD3(+)HLA-DR(+) (activated) T cells and lower antibody levels to mumps and measles at preschool age. Adjusted for confounders, prenatal PCB exposure was associated with less shortness of breath with wheeze, and current PCB body burden was associated with a higher prevalence of recurrent middle-ear infections and of chicken pox and a lower prevalence of allergic reactions. A higher dioxin TEQ was associated with a higher prevalence of coughing, chest congestion, and phlegm. We conclude that in Dutch preschool children the effects of perinatal background exposure to PCBs and dioxins persist into childhood and might be associated with a greater susceptibility to infectious diseases. Common infections acquired early in life may prevent the development of allergy, so PCB exposure might be associated with a lower prevalence of allergic diseases.

Silicosis and coal workers' pneumoconiosis.

Abstract: Exposure to coal mine dust and/or crystalline silica results in pneumoconiosis with initiation and progression of pulmonary fibrosis. This review presents characteristics of simple and complicated coal workers' pneumoconiosis (CWP) as well as pathologic indices of acute and chronic silicosis by summarizing results of in vitro, animal, and human investigations. These results support four basic mechanisms in the etiology of CWP and silicosis: a) direct cytotoxicity of coal dust or silica, resulting in lung cell damage, release of lipases and proteases, and eventual lung scarring; b) activation of oxidant production by pulmonary phagocytes, which overwhelms the antioxidant defenses and leads to lipid peroxidation, protein nitrosation, cell injury, and lung scarring; c) activation of mediator release from alveolar macrophages and epithelial cells, which leads to recruitment of polymorphonuclear leukocytes and macrophages, resulting in the production of proinflammatory cytokines and reactive species and in further lung injury and scarring; d) secretion of growth factors from alveolar macrophages and epithelial cells, stimulating fibroblast proliferation and eventual scarring. Results of in vitro and animal studies provide a basis for proposing these mechanisms for the initiation and progression of pneumoconiosis. Data obtained from exposed workers lend support to these mechanisms.

Health effects of residence near hazardous waste landfill sites: a review of epidemiologic literature.

Abstract: This review evaluates current epidemiologic literature on health effects in relation to residence near landfill sites. Increases in risk of adverse health effects (low birth weight, birth defects, certain types of cancers) have been reported near individual landfill sites and in some multisite studies, and although biases and confounding factors cannot be excluded as explanations for these findings, they may indicate real risks associated with residence near certain landfill sites. A general weakness in the reviewed studies is the lack of direct exposure measurement. An increased prevalence of self-reported health symptoms such as fatigue, sleepiness, and headaches among residents near waste sites has consistently been reported in more than 10 of the reviewed papers. It is difficult to conclude whether these symptoms are an effect of direct toxicologic action of chemicals present in waste sites, an effect of stress and fears related to the waste site, or an effect of reporting bias. Although a substantial number of studies have been conducted, risks to health from landfill sites are hard to quantify. There is insufficient exposure information and effects of low-level environmental exposure in the general population are by their nature difficult to establish. More interdisciplinary research can improve levels of knowledge on risks to human health of waste disposal in landfill sites. Research needs include epidemiologic and toxicologic studies on individual chemicals and chemical mixtures, well-designed single- and multisite landfill studies, development of biomarkers, and research on risk perception and sociologic determinants of ill health.

Associations between air pollution and mortality in Phoenix, 1995-1997.

Abstract: We evaluated the association between mortality outcomes in elderly individuals and particulate matter (PM) of varying aerodynamic diameters (in micrometers) [PM(10), PM(2.5), and PM(CF )(PM(10) minus PM(2.5))], and selected particulate and gaseous phase pollutants in Phoenix, Arizona, using 3 years of daily data (1995-1997). Although source apportionment and epidemiologic methods have been previously combined to investigate the effects of air pollution on mortality, this is the first study to use detailed PM composition data in a time-series analysis of mortality. Phoenix is in the arid Southwest and has approximately 1 million residents (9. 7% of the residents are > 65 years of age). PM data were obtained from the U.S. Environmental Protection Agency (EPA) National Exposure Research Laboratory Platform in central Phoenix. We obtained gaseous pollutant data, specifically carbon monoxide, nitrogen dioxide, ozone, and sulfur dioxide data, from the EPA Aerometric Information Retrieval System Database. We used Poisson regression analysis to evaluate the associations between air pollution and nonaccidental mortality and cardiovascular mortality. Total mortality was significantly associated with CO and NO(2) (p < 0.05) and weakly associated with SO(2), PM(10), and PM(CF) (p < 0. 10). Cardiovascular mortality was significantly associated with CO, NO(2), SO(2), PM(2.5), PM(10), PM(CF) (p < 0.05), and elemental carbon. Factor analysis revealed that both combustion-related pollutants and secondary aerosols (sulfates) were associated with cardiovascular mortality.

Mechanisms underlying Children's susceptibility to environmental toxicants.

Abstract: An important public health challenge has been the need to protect children's health. To accomplish this goal, the scientific community needs scientifically based child-specific risk assessment meth...

Children's exposure assessment: a review of factors influencing Children's exposure, and the data available to characterize and assess that exposure.

Abstract: We review the factors influencing children's exposure to environmental contaminants and the data available to characterize and assess that exposure. Children's activity pattern data requirements are demonstrated in the context of the algorithms used to estimate exposure by inhalation, dermal contact, and ingestion. Currently, data on children's exposures and activities are insufficient to adequately assess multimedia exposures to environmental contaminants. As a result, regulators use a series of default assumptions and exposure factors when conducting exposure assessments. Data to reduce uncertainty in the assumptions and exposure estimates are needed to ensure chemicals are regulated appropriately to protect children's health. To improve the database, advancement in the following general areas of research is required: identification of appropriate age/developmental benchmarks for categorizing children in exposure assessment; development and improvement of methods for monitoring children's exposures and activities; collection of activity pattern data for children (especially young children) required to assess exposure by all routes; collection of data on concentrations of environmental contaminants, biomarkers, and transfer coefficients that can be used as inputs to aggregate exposure models.

Long-term arsenic exposure and incidence of non-insulin-dependent diabetes mellitus: a cohort study in arseniasis-hyperendemic villages in Taiwan.

Abstract: Diabetes prevalence in arseniasis-hyperendemic villages in Taiwan has been reported to be significantly higher than in the general population. The aim of this cohort study was to further evaluate the association between ingested inorganic arsenic and the incidence of non-insulin-dependent diabetes mellitus in these villages. A total of 446 nondiabetic residents in these villages were followed biannually by oral glucose tolerance test. Diabetes is defined as a fasting plasma glucose level > or = 7.8 mmol/L and/or a 2-hr post-load glucose level > or = 11.1 mmol/L. During the follow-up period of 1499.5 person-years, 41 cases developed diabetes, showing an overall incidence of 27.4/1,000 person-years. The incidence of diabetes correlated with age, body mass index, and cumulative arsenic exposure. The multivariate-adjusted relative risks were 1.6, 2.3, and 2.1 for age > or = 55 versus or = 17 versus < 17 mg/L-years, respectively. The incidence density ratios (95% confidence intervals) between the hyperendemic villages and the two nonendemic control townships were 3.6 (3.5-3.6), 2.3 (1.1-4.9), 4.3 (2.4-7.7), and 5.5 (2.2-13.5), respectively, for the age groups of 35-44, 45-54, 55-64, and 65-74 years. The findings are consistent with our previous cross-sectional observation that ingested inorganic arsenic is diabetogenic in human beings.

Roundup inhibits steroidogenesis by disrupting steroidogenic acute regulatory (StAR) protein expression.

Abstract: Recent reports demonstrate that many currently used pesticides have the capacity to disrupt reproductive function in animals. Although this reproductive dysfunction is typically characterized by alterations in serum steroid hormone levels, disruptions in spermatogenesis, and loss of fertility, the mechanisms involved in pesticide-induced infertility remain unclear. Because testicular Leydig cells play a crucial role in male reproductive function by producing testosterone, we used the mouse MA-10 Leydig tumor cell line to study the molecular events involved in pesticide-induced alterations in steroid hormone biosynthesis. We previously showed that the organochlorine insecticide lindane and the organophosphate insecticide Dimethoate directly inhibit steroidogenesis in Leydig cells by disrupting expression of the steroidogenic acute regulatory (StAR) protein. StAR protein mediates the rate-limiting and acutely regulated step in steroidogenesis, the transfer of cholesterol from the outer to the inner mitochondrial membrane where the cytochrome P450 side chain cleavage (P450scc) enzyme initiates the synthesis of all steroid hormones. In the present study, we screened eight currently used pesticide formulations for their ability to inhibit steroidogenesis, concentrating on their effects on StAR expression in MA-10 cells. In addition, we determined the effects of these compounds on the levels and activities of the P450scc enzyme (which converts cholesterol to pregnenolone) and the 3beta-hydroxysteroid dehydrogenase (3beta-HSD) enzyme (which converts pregnenolone to progesterone). Of the pesticides screened, only the pesticide Roundup inhibited dibutyryl [(Bu)(2)]cAMP-stimulated progesterone production in MA-10 cells without causing cellular toxicity. Roundup inhibited steroidogenesis by disrupting StAR protein expression, further demonstrating the susceptibility of StAR to environmental pollutants.