Thereisgrowinginterestinthepossiblehealththreatposedbyendocrine-disruptingchemicals (EDCs), which are substances in our environment, food, and consumer products that interfere with hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostatic control or reproduction. In this first Scientific Statement of The Endocrine Society, we present the evidence that endocrine disruptors have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology. Results from animal models, human clinical observations, and epidemiological studies converge to implicate EDCs as a significant concern to public health. The mechanisms of EDCs involve divergent pathways including (but not limited to) estrogenic, antiandrogenic, thyroid, peroxisome proliferator-activated receptor , retinoid, and actions through other nuclear receptors; steroidogenic enzymes; neurotransmitter receptors and systems; and many other pathways that are highly conserved in wildlife and humans, and which can be modeled in laboratory in vitro and in vivo models. Furthermore, EDCs represent a broad class of molecules such as organochlorinated pesticides and industrial chemicals, plastics and plasticizers, fuels, and many other chemicals that are present in the environment or are in widespread use. We make a number of recommendations to increase understanding of effects of EDCs, including enhancing increased basic and clinical research, invoking the precautionary principle, and advocating involvement of individual and scientific society stakeholders in communicating and implementing changes in public policy and awareness. (Endocrine Reviews 30: 293–342, 2009)

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Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement

This article consists of three parts. Part 1 discusses the Job Content Questionnaire (JCQ), designed to measure scales assessing psychological demands, decision latitude, social support, physical demands, and job insecurity. Part 2 reports the cross-national validity, for men and women, of the JCQ scales in six broadly representative populations from four advanced industrial societies: the United States, Canada, the Netherlands and Japan. JCQ scale means, standard deviations, reliabilities and correlations are compared. Part 3 reviews comparison of the intercountry and interoccupation differences in the scales, discusses specific scales issues and discusses the implications of the study for interpretation of psychosocial job asessment questionnaires.

The Job Content Questionnaire (JCQ): an instrument for internationally comparative assessments of psychosocial job characteristics.

Disinfection by-products (DBPs) are formed when disinfectants (chlorine, ozone, chlorine dioxide, or chloramines) react with naturally occurring organic matter, anthropogenic contaminants, bromide, and iodide during the production of drinking water. Here we review 30 years of research on the occurrence, genotoxicity, and carcinogenicity of 85 DBPs, 11 of which are currently regulated by the U.S., and 74 of which are considered emerging DBPs due to their moderate occurrence levels and/or toxicological properties. These 74 include halonitromethanes, iodo-acids and other unregulated halo-acids, iodo-trihalomethanes (THMs), and other unregulated halomethanes, halofuranones (MX [3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone] and brominated MX DBPs), haloamides, haloacetonitriles, tribromopyrrole, aldehydes, and N-nitrosodimethylamine (NDMA) and other nitrosamines. Alternative disinfection practices result in drinking water from which extracted organic material is less mutagenic than extracts of chlorinated water. However, the levels of many emerging DBPs are increased by alternative disinfectants (primarily ozone or chloramines) compared to chlorination, and many emerging DBPs are more genotoxic than some of the regulated DBPs. Our analysis identified three categories of DBPs of particular interest. Category 1 contains eight DBPs with some or all of the toxicologic characteristics of human carcinogens: four regulated (bromodichloromethane, dichloroacetic acid, dibromoacetic acid, and bromate) and four unregulated DBPs (formaldehyde, acetaldehyde, MX, and NDMA). Categories 2 and 3 contain 43 emerging DBPs that are present at moderate levels (sub- to low-mug/L): category 2 contains 29 of these that are genotoxic (including chloral hydrate and chloroacetaldehyde, which are also a rodent carcinogens); category 3 contains the remaining 14 for which little or no toxicological data are available. In general, the brominated DBPs are both more genotoxic and carcinogenic than are chlorinated compounds, and iodinated DBPs were the most genotoxic of all but have not been tested for carcinogenicity. There were toxicological data gaps for even some of the 11 regulated DBPs, as well as for most of the 74 emerging DBPs. A systematic assessment of DBPs for genotoxicity has been performed for approximately 60 DBPs for DNA damage in mammalian cells and 16 for mutagenicity in Salmonella. A recent epidemiologic study found that much of the risk for bladder cancer associated with drinking water was associated with three factors: THM levels, showering/bathing/swimming (i.e., dermal/inhalation exposure), and genotype (having the GSTT1-1 gene). This finding, along with mechanistic studies, highlights the emerging importance of dermal/inhalation exposure to the THMs, or possibly other DBPs, and the role of genotype for risk for drinking-water-associated bladder cancer. More than 50% of the total organic halogen (TOX) formed by chlorination and more than 50% of the assimilable organic carbon (AOC) formed by ozonation has not been identified chemically. The potential interactions among the 600 identified DBPs in the complex mixture of drinking water to which we are exposed by various routes is not reflected in any of the toxicology studies of individual DBPs. The categories of DBPs described here, the identified data gaps, and the emerging role of dermal/inhalation exposure provide guidance for drinking water and public health research.

Occurrence, genotoxicity, and carcinogenicity of regulated and emerging disinfection by-products in drinking water: a review and roadmap for research.

Men at risk: occupation and male infertility☆

Numerous reports have recently focused on various aspects of adverse trends in male reproductive health, such as the rising incidence of testicular cancer; low and probably declining semen quality; high and possibly increasing frequencies of undescended testis and hypospadias; and an apparently growing demand for assisted reproduction. Due to specialization in medicine and different ages at presentation of symptoms, reproductive problems used to be analysed separately by various professional groups, e.g. paediatric endocrinologists, urologists, andrologists and oncologists. This article summarizes existing evidence supporting a new concept that poor semen quality, testis cancer, undescended testis and hypospadias are symptoms of one underlying entity, the testicular dysgenesis syndrome (TDS), which may be increasingly common due to adverse environmental influences. Experimental and epidemiological studies suggest that TDS is a result of disruption of embryonal programming and gonadal development during fetal life. Therefore, we recommend that future epidemiological studies on trends in male reproductive health should not focus on one symptom only, but be more comprehensive and take all aspects of TDS into account. Otherwise, important biological information may be lost.

Testicular dysgenesis syndrome ; an increasingly common developmental disorder with environmental aspects

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.

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

In 1992 a worldwide decline in sperm density was reported; this was quickly followed by numerous critiques and editorials. Because of the public health importance of this finding, a detailed reanalysis of data from 61 studies was warranted to resolve these issues. Multiple linear regression models (controlling for abstinence time, age, percent proven fertility, specimen collection method, study goal and location) were used to examine regional differences and the interaction between region (United States, Europe, and non-Western countries) and year. Nonlinear models and residual confounding were also examined in these data. Using a linear model (adjusted R2 = 0. 80), means and slopes differed significantly across regions (p = 0. 02). Mean sperm densities were highest in Europe and lowest in non-Western countries. A decline in sperm density was seen in the United States (studies from 1938-1988; slope = -1.50; 95% confidence interval (CI), -1.90--1.10) and Europe (1971-1990; slope = -3.13; CI, -4.96- -1.30), but not in non-Western countries (1978-1989; slope = 1.56; CI, -1.00-4.12). Results from nonlinear models (quadratic and spline) were similar. Thus, further analysis of these studies supports a significant decline in sperm density in the United States and Europe. Confounding and selection bias are unlikely to account for these results. However, some intraregional differences were as large as mean decline in sperm density between 1938 and 1990, and recent reports from Europe and the United States further support large interarea differences in sperm density. Identifying the cause(s) of these regional and temporal differences, whether environmental or other, is clearly warranted.

Have sperm densities declined? A reanalysis of global trend data.

Objective. —To determine, in a multivariate analysis, risk factors for preeclampsia that could be observed early in pregnancy and to establish whether these risk factors are different for nulliparas and multiparas. Design. —A case-control study of preeclampsia. Setting. —Women who gave birth at Northern California Kaiser Permanente Medical Centers in 1984 and 1985. Participants. —Preeclamptic cases (n =139) were determined from discharge diagnosis of severe preeclampsia and by confirmation of blood pressures and proteinuria from medical records. Controls (n = 132) were randomly selected women who had no discharge diagnosis of any hypertensive disorder of pregnancy and who had no evidence of hypertension or proteinuria from medical record review. Main Variables Examined. —Medical records were abstracted for information regarding maternal age, race, previous pregnancy history, family medical history, socioeconomic status, employment during pregnancy, body mass, and smoking and alcohol consumption. Results. —Multiple logistic regression analyses confirmed that case patients were more likely than control patients to be nulliparous (adjusted odds ratio [OR], 5.4; 95% confidence interval [CI], 2.8 to 10.3) and that preeclampsia in a previous pregnancy greatly increased the risk in a subsequent one (adjusted OR, 10.8; 95% CI, 1.2 to 29.1). However, regardless of parity, preeclamptic women were also more likely to be of high body mass (adjusted OR, 2.7; 95% CI, 1.2 to 6.2), to work during pregnancy (adjusted OR, 2.1; 95% CI, 1.1 to 4.4), and to have a family history of hypertension (adjusted OR, 1.7; 95% CI, 0.92 to 3.2). Having a previous history of a spontaneous abortion was protective but only in multiparous women (adjusted OR for multiparas, 0.09; 95% CI, 0.02 to 0.48). In contrast, being black was a significant risk for preeclampsia but only in nulliparous women (adjusted OR for nulliparas, 12.3; 95% CI, 1.6 to 100.8). Conclusions. —There are a number of risk factors for preeclampsia that may be determined early in a woman's pregnancy. Multiparas and nulliparas share certain risk factors but not others. A cohort investigation is needed to determine the ability of these risk factors to predict who develops preeclampsia. (JAMA. 1991;266:237-241)

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=jama&articleId=386464&pdfFileName=jama_266_2_033.pdf

A multivariate analysis of risk factors for preeclampsia.

We examined the association of exposure to environmental tobacco smoke with birth weight and gestational age in a large, prospective study We also compared these endpoints between infants of active maternal smokers and those of non-smoking, non-ETS exposed women Pregnant women were interviewed by telephone during the first trimester, and pregnancy outcome was determined for 99% Among the 4,454 singleton live births that could be linked to their birth certificate, we confirmed increased risks of low birth weight and small for gestational age with heavier maternal smoking (> 10 cigarettes/day), as well as noting an increased risk for "very preterm" birth ( or = 30 years) than those of younger mothers, as well as among non-whites High environmental tobacco smoke exposure (> or = 7 hours/day in non-smokers) was moderately associated with low birth weight (adjusted odds ratio (AOR) 18, 95% confidence limits (95% CL) = 082, 41), preterm birth (AOR 16, 95% CL = 087, 29), and most strongly with very preterm birth (AOR 24, 95% CL = 10, 53) These associations were generally greater among non-whites than whites The data support earlier studies suggesting that prenatal environmental tobacco smoke exposure, in addition to maternal smoking, affects infant health

Prenatal active or passive tobacco smoke exposure and the risk of preterm delivery or low birth weight.

OBJECTIVE. We investigated the relationship between prenatal exposure to dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE) and neurodevelopment of Mexican farm-workers9 children in California. METHODS. Participants from the Center for the Health Assessment of Mothers and Children of Salinas study, a birth cohort study, included 360 singletons with maternal serum measures of p,p′-DDT, o,p′-DDT, and p,p′-DDE. Psychomotor development and mental development were assessed with the Bayley Scales of Infant Development at 6, 12, and 24 months. RESULTS. We found a ∼2-point decrease in Psychomotor Developmental Index scores with each 10-fold increase in p,p′-DDT levels at 6 and 12 months (but not 24 months) and p,p′-DDE levels at 6 months only. We found no association with mental development at 6 months but a 2- to 3-point decrease in Mental Developmental Index scores for p,p′-DDT and o,p′-DDT at 12 and 24 months, corresponding to 7- to 10-point decreases across the exposure range. Even when mothers had substantial exposure, breastfeeding was usually associated positively with Bayley scale scores. CONCLUSIONS. Prenatal exposure to DDT, and to a lesser extent DDE, was associated with neurodevelopmental delays during early childhood, although breastfeeding was found to be beneficial even among women with high levels of exposure. Countries considering the use of DDT should weigh its benefit in eradicating malaria against the negative associations found in this first report on DDT and human neurodevelopment.

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In utero exposure to dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE) and neurodevelopment among young Mexican American children.

Laura Fenster

Papers

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

Have sperm densities declined? A reanalysis of global trend data.

A multivariate analysis of risk factors for preeclampsia.

Prenatal active or passive tobacco smoke exposure and the risk of preterm delivery or low birth weight.

In utero exposure to dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE) and neurodevelopment among young Mexican American children.