Evolution of DOHaD: the impact of environmental health sciences.

Environmental exposures have a significant influence on the chronic health conditions plaguing children and adults. Although the Developmental Origins of Health and Disease (DOHaD) paradigm historically has focused on nutrition, an expanding body of research specifically communicates the effects of chemical exposures on early-life development and the propagation of non-communicable disease across the lifespan. This paper provides an overview of 20 years of research efforts aimed at identifying critical windows of susceptibility to environmental exposures and the signaling changes and epigenetic influences associated with disease progression. DOHaD grants funded by the National Institute of Environmental Health Sciences (NIEHS) in 1991, 2001 and 2011 are identified by grant-analysis software, and each portfolio is analyzed for exposures, disease endpoints, windows of exposure, study design and impact on the field based on publication data. Results show that the 1991 and 2001 portfolios comprised metals, PCBs and air pollutants; however, by 2011, the portfolio has evolved to include or expand the variety of endocrine disruptors, pesticides/persistent organic pollutants and metals. An assortment of brain-health endpoints is most targeted across the portfolios, whereas reproduction and cancer increase steadily over the same time period, and new endpoints like obesity are introduced by 2011. With mounting evidence connecting early-life exposures to later-life disease, we conclude that it is critical to expand the original DOHaD concept to include environmental chemical exposures, and to continue a research agenda that emphasizes defining sensitive windows of exposure and the mechanisms that cause disease.

Long-term assessment of efficacy of permeable pond covers for odour reduction.

Three anaerobic ponds used to store and treat piggery wastes were fully covered with permeable materials manufactured from polypropylene geofabric, polyethylene shade cloth and supported straw. The covers were assessed in terms of efficacy in reducing odour emission rates over a 40-month period. Odour samples were collected from the surface of the covers, the surface of the exposed liquor and from the surface of an uncovered (control) pond at one of the piggeries. Relative to the emission rate of the exposed liquor at each pond, the polypropylene, shade cloth and straw covers reduced average emission rates by 76%, 69% and 66%, respectively. At the piggery with an uncovered control pond, the polypropylene covers reduced average odour emission rates by 50% and 41%, respectively. A plausible hypothesis, consistent with likely mechanisms for the odour reduction and the olfactometric method used to quantifying the efficacy of the covers, is offered.

Applying genomic technologies in environmental health research: challenges and opportunities.

Recent discoveries in molecular biology and genetics have made it possible for environmental health researchers to examine how genetic characteristics affect response to environmental exposures. Understanding such gene-environment interactions offers exciting possibilities for the prevention and control of environmentally induced diseases. Despite these potential benefits, the collection and analysis of genetic information in environmental health research presents many of the same ethical, legal, and social (ELSI) challenges found in other types of genetic research. In this article, we describe a number of ELSI challenges in environmental genomic research and the opportunities and responsibilities that accompany this research.

1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene and polychlorinated biphenyls and breast cancer: combined analysis of five U.S. studies.

BACKGROUND: Environmental exposure to organochlorines has been examined as a potential risk factor for breast cancer. In 1993, five large U.S. studies of women located mainly in the northeastern United States were funded to evaluate the association of levels of 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene (DDE) and polychlorinated biphenyls (PCBs) in blood plasma or serum with breast cancer risk. We present a combined analysis of these results to increase precision and to maximize statistical power to detect effect modification by other breast cancer risk factors. METHODS: We reanalyzed the data from these five studies, consisting of 1400 case patients with breast cancer and 1642 control subjects, by use of a standardized approach to control for confounding and assess effect modification. We calculated pooled odds ratios (ORs) and 95% confidence intervals (CIs) by use of the random-effects model. All statistical tests were two-sided. RESULTS: When we compared women in the fifth quintile of lipid-adjusted values with those in the first quintile, the multivariate pooled OR for breast cancer associated with PCBs was 0.94 (95% CI = 0.73 to 1.21), and that associated with DDE was 0.99 (95% CI = 0.77 to 1.27). Although in the original studies there were suggestions of elevated breast cancer risk associated with PCBs in certain groups of women stratified by parity and lactation, these observations were not evident in the pooled analysis. No statistically significant associations were observed in any other stratified analyses, except for an increased risk with higher levels of PCBs among women in the middle tertile of body mass index (25-29.9 kg/m(2)); however, the risk was statistically nonsignificantly decreased among heavier women. CONCLUSIONS: Combined evidence does not support an association of breast cancer risk with plasma/serum concentrations of PCBs or DDE. Exposure to these compounds, as measured in adult women, is unlikely to explain the high rates of breast cancer experienced in the northeastern United States.

The National Institute of Environmental Health Sciences' research program on children's environmental health.

This article highlights the wide array of research programs supported by the National Institute of Environmental Health Sciences (NIEHS) that address issues related to children's environmental health. Special attention is given to the interagency, collaborative Centers for Children's Environmental Health and Disease Prevention Research program. A brief description of each of the eight centers highlights scientific foci and research efforts to date. In addition to discussing NIEHS-supported research programs, the article emphasizes the NIEHS' commitment to the promotion of translating basic research findings into public health knowledge so that culturally sensitive and applicable interventions may be developed.

Genes and the environment: their impact on children's health.

Because the human population is biologically diverse and genetically heterogeneous, it is not surprising that differences in susceptibility to disease among individuals with or without exposure to environmental agents exist. Individuals vary greatly in their susceptibility to disease. This is true of adults and children. The etiologies of many diseases of childhood are due to a combination of factors, including genetic susceptibility and environmental exposures during vulnerable periods of development. Genes regulate cellular growth and development, DNA replication and repair, the metabolism of endogenous agents in the body, and the metabolism and excretion of exogenous agents that the body comes in contact with in the environment. This regulation varies over the life span, contributing to the cellular consequences of the environmental exposures. This paper summarizes the contributions of genetics in understanding the etiology of environmentally induced diseases in children. The use of biomarkers of genetic susceptibility in the study of these diseases will be discussed. Future research needs for expanding our knowledge of the interactions between genetic and environmental components of childhood diseases will be presented.

Human biomonitoring: research goals and needs.

Epidemiological studies have taken advantage of a number of strategies to monitor human populations for mortality, incidence, and exposure to hazardous environmental agents. These studies have been compromised by the lack of individual exposure assessment data that precisely quantified internal dose. As methods improve in analytical chemistry and molecular biology, direct biological monitoring of exposed populations is possible. Biomarkers have been developed and validated in exposed populations that quantify individual exposure, susceptibility, and early markers of health effects and can be used to study relationships between exposures and environmentally induced diseases. This paper provides background on the state of the art of human populations monitoring and, through a series of case studies, provides examples of novel biomarkers of exposure, susceptibility, and effect that highlight new opportunities for biomonitoring. Prevention of human disease due to environmental contaminants can be accomplished by implementing strategies such as those discussed to monitor exposure and early health effects in human populations.

Breast cancer and environmental risk factors: epidemiological and experimental findings.

Breast cancer has long been associated with reproductive hormone exposures. Recently, greater attention has been focused on environmental exposures that may be responsible for some proportion of breast cancer incidence. Several etiologic aspects are discussed. A number of chemicals induce breast cancer in rodents--including solvents, pesticides, and polycyclic aromatic hydrocarbons--and these might serve as leads for studies in humans. In women, strong links have been established between breast cancer risk and ionizing radiation. Evidence for nonionizing radiation (electromagnetic field) exposures and breast cancer is suggestive, albeit limited. Occupational exposures have not been identified as breast cancer risks, but several associations need further study, including solvents and pesticides. Time of life when exposures take place is important, and this claim is strongly supported by data on cigarette smoking and radiation. Also, basic research has demonstrated that mammary tissue is more susceptible to carcinogenesis at certain periods of breast development. Likewise, prenatal, neonatal, and adolescent exposures deserve continuing attention. Research on etiology of breast cancer should measure environmental exposures and take into account the time of life at which these occur. Complex interactions between exogenous and endogenous carcinogenic agents need further focus, as modulated by varying genetically determined individual susceptibilities.

Childhood cancer mortality and radon concentration in drinking water in North Carolina.

We explored the association between groundwater radon levels and childhood cancer mortality in North Carolina. Using data from two state-wide surveys of public drinking water supplies, counties were ranked according to average groundwater radon concentration. Age and sex-adjusted 1950-79 cancer death rates among children under age 15 were calculated for counties with high, medium, and low radon levels. Overall cancer mortality was increased in counties with medium and high radon levels. The strongest association was for the leukaemias, but risks were also suggested for other sites. These associations could be due to confounding or other biases, but the findings are consistent with other recent reports.

Relationship of mortality, occupation, and pulmonary diffusing capacity to pleural thickening in the First National Health and Nutrition Examination Survey.

We studied the relationship of pleural thickening consistent with asbestos exposure to mortality, career employment in asbestos-related jobs, and pulmonary diffusing capacity among participants in the first National Health and Nutrition Examination Survey. Three "B" readers examined chest X-rays to identify 59 individuals with such pleural abnormalities. From 1975 to 1984, the all-cause mortality rate ratio (RR) comparing males with and without occupational pleural thickening was 1.3 (95% C.I. 0.8-2.2). For lung cancer, the mortality RR for males was 3.0 (95% C.I. 1.0-9.1). Career asbestos work was not associated with occupational pleural thickening among men, probably because some with the condition had only short-term exposure to asbestos. Pulmonary diffusing capacity was lower in those with occupational pleural thickening, taking smoking into account. These results suggest that individuals in the general population who have occupational pleural thickening are at risk for some of the health consequences of asbestos work, including lung cancer, even if they were not career asbestos workers.

Sunlight and other risk factors for cataracts: an epidemiologic study.

A case control study was conducted in North Carolina to explore the relation between individual exposure to sunlight and the risk of cataracts. One hundred thirteen cases and 161 controls aged 40-69 at diagnosis were studied. Sunlight exposure was inferred from interview data on residency and time spent in the sun, combined with solar radiation data from the National Climatic Data Center. Sunlight exposure was very slightly related to all types of opacities combined. Although the numbers of cases with each type of opacity was small, the risk of cataracts was slightly increased in medium and high exposure categories for persons having cortical or posterior subcapsular opacities only, but not nuclear sclerotic changes. Persons with dark brown or hazel eyes are at increased risk. An unexpected finding was that persons who reported using tranquilizers for six months were at increased risk.

Radon-222 concentration in groundwater and cancer mortality in North Carolina.

In a geographic correlation study, we explored the possibility that residential exposure to radon in groundwater may be related to cancers other than lung cancer. Measurements of radon in groundwater and 1978-1982 cancer mortality data from North Carolina, USA were used to investigate this relationship. Counties were categorized in two levels of radon exposure according to measured radon concentration and geology. In the lower exposure group (unexposed) county mean radon concentrations ranged from 0-228 pCi/l (0-8436 Bq/m3), and in the upper group (potentially exposed) the range of county average concentrations was 229-10892 pCi/l (8473-403004 Bq/m3) (median 1375 pCi/l (50875 Bq/m3)). Adjusted mortality ratios and 95% confidence intervals were calculated for selected cancers, including leukemias, gastro-intestinal tract cancers, and respiratory tract cancers excluding lung cancer. In contrast to other ecologic studies, we found no consistent association between radon level and cancer mortality.

Cytogenetic and chemical detection of human exposure to polyhalogenated aromatic hydrocarbons.

Peripheral lymphocytes from Taiwanese women (n = 35) exposed to polychlorinated aromatic hydrocarbons and from matched controls (n = 24) were assessed for the levels of sister chromatid exchanges (SCEs) after a 72-hour incubation of whole blood in the presence or absence of alpha-naphthoflavone (ANF) and for chromosome aberrations after 48 hours of incubation. Serum levels of polychlorinated biphenyl (PCB) congeners were measured for all individuals, and serum levels of several polychlorinated dibenzofurans (PCDFs) were measured for 12 exposed individuals by gas chromatography-mass spectometry. Blood concentrations of total PCBs in the exposed population averaged approximately 15 ppb, whereas mean PCDF values were 14 ppt. Major PCB congeners detected were 2,2' 4,4', 5,5'-hexa CB and 2,2'3,4,4',5-hexa CB. PCDFs detected were primarily 1,2,3,4,7,8,-hexachlorodibenzofuran (10.8 ppt) and 2,3,4,7,8-pentachlorodibenzofuran (2.7 ppt). Average SCE frequencies were 7.61 for controls and 7.30 for exposed individuals when assays were conducted in the absence of ANF, whereas respective values were 8.85 and 10.75 in the presence of ANF. Differences in the level of ANF-induced SCEs between the two populations were highly significant (P less than .001). Moreover, the ANF-induced SCEs were highly correlated with the serum concentrations of total PCBs and of several PCB congeners (P less than .001). Increases in ANF-induced SCEs appeared to be linear up to a PCB concentration of approximately 30 ppb. Chromosome aberration frequencies were similar in control and exposed populations. These studies demonstrate that in vivo exposure to PCBs and PCDFs result in an enhanced sensitivity of lymphocytes to the SCE-causing actions of ANF.

Effects of alpha-naphthoflavone on levels of sister chromatid exchanges in lymphocytes from active and passive cigarette smokers: dose-response relationships.

The frequency of sister chromatid exchanges (SCE) were determined in lymphocytes of nonsmokers, passive smokers, and active smokers in the presence and absence of alpha-naphthoflavone (ANF). Higher levels of SCEs were detected for all smoking groups after in vitro addition of ANF when compared with an assay without ANF. There was a highly statistically significant difference between heavy smokers and nonsmokers (9.25 versus 7.43 SCE/cell) for the assay without ANF and for the ANF assay (14.2 versus 8.8). When considering the numerical difference in SCEs between the assays with and without ANF (delta SCE), higher values were noted for moderate smokers (2.7) and heavy smokers (4.9) compared to nonsmokers (1.4). Significant dose-response relationships were found between the frequency of SCEs and factors related to smoking, such as duration and frequency of cigarette use, tar, nicotine, carbon monoxide content of brand, and urinary measures of nicotine metabolites (cotinine and thiocyanate). No elevation of SCEs in passive smokers was found when compared to nonsmokers using either assay. The mechanism for SCE enhancement by ANF is unclear, but may be related to metabolic activation of the ANF by the cytochrome P-450 system in lymphocytes. The dosimetry relationships between cigarette smoke exposure and SCE frequency indicate that culture of human lymphocytes via ANF may provide a sensitive tool to detect exposure to cigarette smoke.