Harvard University (School of Public Health)

Kresge Center for Environmental Health

Douglas Dockery, Ph.D.
ddockery@hsph.harvard.edu
http://www.hsph.harvard.edu/niehs/

Project Description

The Kresge Center for Environmental Health fosters active collaborations among three Research Cores: 1) Metals, 2) Urban and Occupational Particles, and 3) Organic Pollutants. The work of the Research Cores is greatly enhanced by three Facility Cores: 1) Biological Analyses, 2) Exposures and Environmental Analyses, and 3) Environmental Statistics. Finally, the investigators' ability to make their research and knowledge available to the public is greatly enhanced by the Community Outreach and Education Program (COEP). Other Center activities, such as pilot projects, new investigators, and program enrichment are catalytic mechanisms to achieve integration, interaction, productive, and innovative science. The objectives of this Core Center are to generate new knowledge relating to the physiology, pharmacology, pathology, cell biology, molecular biology, genetics, and epidemiology of environmental disease, and to apply this knowledge to new modalities of prevention, diagnosis, and therapy. The investigators achieve these objectives through a variety of approaches, which range from studies of molecules and cells to those of whole animals and human populations. Through the organizational structure and financial support provided by the NIEHS Center Grant, the investigators' increase the impact of their research and teaching in environmental health. The Harvard NIEHS Center for Environmental Health continues to be a major focal point for environmental research and training in Boston.

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Project Highlights

Health Effects of Ambient Particulate Matter (PM)

Community-based particulate air pollution epidemiological analyses focus on understanding the pathways of the observed associations between particulate air pollution and acute mortality and morbidity and on identifying the susceptible portions of the population.  An adjacent objective is to characterize the mechanisms responsible for these health effects.

Pooled analyses from multiple cities continue to provide new insights.  Particles were associated with admissions for heart failure (Wellenius et al 2006), respiratory disease (Medina-Ramon et al 2006), and heart disease (Barnett et al 2006).  Case-crossover methodology was used to examine individual modifiers of the effect of particles on mortality (Zeka et al 2006).  The association between PM2.5 and both all-cause and specific-cause mortality using over 1.3 million deaths in 27 US communities between 1997 and 2002 was examined (Franklin et al 2006).  A two-stage approach was used.  First, the association between PM2.5 and mortality in each community was quantified using a case-crossover design.  Second, meta-analysis was used to estimate a summary effect over all 27 communities.  Effect modification of age and gender was examined using interaction terms in the case-crossover model, while effect modification of community-specific characteristics including geographic location, annual PM2.5 concentration above 15 mug/m3 and central air conditioning prevalence was examined using meta-regression.  A 1.21% (95% CI 0.29, 2.14%) increase in all-cause mortality, a 1.78% (95% CI 0.20, 3.36%) increase in respiratory related mortality and a 1.03% (95% CI 0.02, 2.04%) increase in stroke related mortality with a 10 mug/m3 increase in previous day’s PM2.5 were observed.  The magnitude of these associations is more than triple that recently reported for PM10, suggesting that combustion and traffic related particles are more toxic than larger sized particles.  Effect modification occurred in all-cause and specific-cause deaths with greater effects in subjects >/=75 years of age.  There was suggestive evidence that women may be more susceptible to PM2.5 effects than men.  Increased prevalence of central air conditioning was associated with a decreased effect of PM2.5.  These findings suggest that PM2.5 may pose a public health risk even at or below current ambient levels.

Medina-Ramon et al (2006) conducted a case-crossover study in 36 US cities to evaluate the effect of ozone and particulate matter (PM10) on respiratory hospital admissions.  The study confirmed that exposure to ozone and PM10 is associated with respiratory hospital admissions, and provided evidence that the effect of air pollution is modified by certain city characteristics, such as the likelihood of central air conditioning and the variability of summer temperatures.

Zeka et al (2006) examined individual modifiers in a case-crossover study of 20 US cities.  PM10 mortality was influenced by gender and age and the level of education was inversely related to the risk of PM10 associated mortality.  A diagnosis of diabetes modified the effect of PM10 for respiratory and stroke mortality.  These findings suggest that more attention must be paid to population characteristics to better understand susceptibility.

Dubowsky SD, Suh H, Schwartz J, Coull BA, and Gold DR.  Diabetes, obesity, and hypertension may enhance associations between air pollution and markers of systemic inflammation.  Environ Health Perspect.  2006; 114(7):992-8.

Laden F, Schwartz J, Speizer FE, Dockery DW.  Reduction in fine particulate air pollution and mortality: Extended follow-up of the Harvard Six Cities study.  Am J Respir Crit Care Med.  2006; 173:1-6.

Wellenius GA, Coull BA, Batalha JRF, Diaz EA, Lawrence J, Godleski JJ.  Effects of ambient particles and carbon monoxide on supraventricular arrhythmias in a rat model of myocardial infarction.  Inhal Toxicol.  2006; 18(14):1077-82.

Zeka A, Zanobetti A, Schwartz J.  Individual modifiers of the effects of particulate matter on daily mortality.  Am J Epidemiol.  2006; 163:849-59.

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Organic Pollutants, Children’s Health, and Reproductive Health

Environmental PCB and Phthalate Reproductive Health Study
Phthalates are ubiquitous compounds for which there is limited human data.  The recent CDC analysis of NHANES 2001-2002 participants for phthalates showed that a large proportion of the general population is exposed to phthalates.  Dr. Hauser recently published two manuscripts on the relationship between phthalates and altered semen quality, confirming his previous findings and extending the results to include the analysis of additional metabolites.  This allowed for an in depth exploration of metabolic phenotypes in relation to risk of poorer semen quality.  Men that were poor metabolizers of phthalates to the oxidative metabolites were found to be at increased risk of sperm DNA damage for a given exposure to di(2-ethylhexyl) phthalate.

Organophosphate Exposure and Semen Quality Study
Based on results from our pilot study examining pyrethroids organophosphates (OP) (Perry et al., 2007), we conducted a case control study of OP exposure and semen quality among Chinese men (unpublished data in preparation).  367 urine samples with sperm concentration and motility were available for analysis.  Motility and concentration distributions were regressed after adjusting for age, alcohol drinking, passive smoking, education, occupational chemical exposures, active smoking, abstinence from sexual activity, and time delay from ejaculation to laboratory analysis of sperm.  Cases were defined as those below the median percent motile and median concentration whereas controls were defined as above the median for motility and concentration.  94 and 95 cases and controls were identified respectively and urinalyses were performed to analyze levels of OP metabolites.  Covariates in the adjusted model included age, self reported alcohol use, passive smoke exposure, education, occupational exposure to chemicals, current smoking, and abstinence days as well as time from sperm sample collection to lab analysis.  After adjustment, men with lower semen quality (cases) had significantly higher levels of dimethylphosphate (DMP) urinary metabolites as compared to men with higher semen quality (controls).

Organochlorines and Reproductive Health among Women
In another collaborative study among Center investigators, we are exploring the relationship of organochlorines with women’s reproductive health among Chinese textile workers. Over the past year we have demonstrated a number of important findings.  First, we demonstrated a positive, monotonic, exposure-response association between preconception serum DDT levels and the risk of subsequent early (pre-clinical) pregnancy loss (OR=1.17, 95% CI: 1.05, 1.29 for each 10 ng/g increase in serum DDT) (Venners et al., 2006).   This finding is of note given that previous studies have been unable to detect pre-clinical losses; furthermore, previous inconsistencies in findings for DDT-associated risk of clinical miscarriage may be a consequence of more potent DDT-associated increased risk of pre-clinical losses.  Second, we demonstrated an inverse association of serum DDT with BMI among these lean, reproductive age women prior to pregnancy, an association consistent with distribution and elimination kinetics characteristic of relatively recent peak DDT exposures (Perry et al., 2006).  Furthermore, there was evidence of significant secular declines in exposure risk in this population consistent with declining agricultural uses of DDT in China.  Third, we found DDT associated decreases in urinary estrogen and progesterone metabolites after adjusting for menstural cycle phase (Perry et al., 2006). 

Hauser R, Meeker JD, Singh NP, Silva MJ, Ryan L, Duty S, Calafat AM.  DNA damage in human sperm is related to urinary levels of phthalate monoester and oxidative metabolites.  Human Reprod.  2007; 22:688-95.

Hauser R, Meeker JD, Duty S, Silva M, Calafat A.  Altered semen quality in relation to urinary levels of phthalate monoester and oxidative metabolites.  Epidemiology.  2006; 17:682-91.

Perry MJ, Ouyang F, Chen C, Venners S, Korrick S, Xu X, Lasley B, Wang X.  A prospective study of serum DDT and progesterone and estrogen levels across the menstrual cycle in nulliparous women of reproductive age.  Am J Epidemiol 2006; 164(11):1056-64.

Perry MJ, Venners SA, Barr DB, Xu X.  Organophosphorous and pyrethroid insecticide exposures and   male reproduction.  Repro Toxicol 2007; 23(1):113-18.

Perry MJ, Ouyang F, Chen C, Venners S, Korrick S, Xu X, Lasley B, Wang X.  A prospective study of serum DDT and progesterone and estrogen levels across the menstrual cycle in nulliparous women of reproductive age.  Am J Epidemiol.  2006; 164(11):1056-64.

Venners S, Liu X, Perry MJ, Korrick S, Li Z, Yang F, Yang J, Lasley B, Xu X, Wang X. Urinary estrogen and progesterone metabolite concentrations in menstrual cycles of fertile women with non-conception, early pregnancy loss or clinical pregnancy.  Hum Repro 2006; 21(9):2272-80.

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