2005 Progress Report: Latent Effects of Gestational Exposure to Heptachlor

EPA Grant Number: R829439
Title: Latent Effects of Gestational Exposure to Heptachlor
Investigators: Baker, Dean , Gollapudi, Sastry , Kesner, James , Luderer, Ulrike , Yang, Haiou
Institution: University of California - Irvine , National Institute for Occupational Safety and Health
EPA Project Officer: Carleton, James N
Project Period: March 1, 2002 through February 28, 2005 (Extended to August 31, 2006)
Project Period Covered by this Report: March 1, 2005 through February 28, 2006
Project Amount: $1,931,310
RFA: Endocrine Disruptors: Epidemiologic Approaches (2001) RFA Text |  Recipients Lists
Research Category: Health , Safer Chemicals , Endocrine Disruptors


The objective is to determine whether gestational exposure to the cyclodiene insecticide heptachlor permanently alters reproductive and immune function. The study is based on a unique, well-characterized episode in which the entire commercial milk supply on the Hawaiian island of Oahu was contaminated with heptachlor epoxide during a 15-month period (1981–1982), resulting in gestational exposure to offspring of women who drank cows’ milk during that period. The study is using a population of 1,891 young adults, born between July 1981 and June 1982, who participated in an earlier study of the neurobehavioral effects of this exposure. The target for the study population is 400 young adults who were born on Oahu and 200 comparison participants who were not born on Oahu.

The study will assess sensitive biological indicators of reproductive and immune function, including: serum reproductive hormone concentrations—testosterone in men, estradiol and progesterone in women, and luteinizing hormone and follicle-stimulating hormone in both men and women; semen samples in men; and one menstrual cycle of daily urine specimens in women to measure levels of luteinizing hormone, estrone-3-glucuronide (EG), and pregnanediol 3-alpha-glucuronide (PG). Indicators of immune function include measurement of cutaneous delayed hypersensitivity reaction to recall antigens, antibody titer response to immunization with tetanus and multivalent pneumococcal vaccine, and the proportion of Th1 and Th2 type CD4+ cell subsets in the peripheral blood.

The analysis will compare reproductive and immune function measures between the Oahu-born and non-Oahu born participants, controlling for relevant confounders. Estimates of gestational heptachlor epoxide exposure during the milk contamination will be modeled based on exposure data obtained in earlier studies and on historical data of pesticide concentration in the contaminated milk.

Progress Summary:

By the end of the reporting period, we attempted to trace and recruit all 1,891 potential participants in the recruitment database, which was generated from our earlier neurobehavioral project. We were able to contact 1,123 potential participants and concluded that 768 were not reachable after attempting multiple phone calls and letter contacts. Of the contacted persons, we were able to recruit and enroll 351 participants; 354 were not willing to take part in the study, 367 were not eligible, and 51 were lost to recruitment after being contacted.

We continued to explore strategies to improve participant recruitment. A major activity during the project year 4 was to process a Hawaii Department of Education database for additional potential participants. This database included 17,568 students who met the project birth date specification (July 01, 1981–June 30, 1982) from 164 elementary schools, middle schools, and high schools on Oahu. Within this database, we selected 11,344 records of past graduates from high schools. We screened out students from special education programs (who were not eligible for the earlier neurobehavioral study) and the persons who were already included in the existing project database, leaving a pool of 9,022 potentially eligible participants. We sent out batches of 200 to 300 information letters once every 2 weeks to this pool of potential participants. Even with the substantial effort of data processing, letter mailing, and followup, the yield was low, yielding only 106 additional participants who enrolled in the project.

As of February 28, 2006, the number of participants for the study was 457, of whom 249 were male and 208 were female. We collected 457 participant questionnaires and 390 parent questionnaires. To evaluate the integrity of cell-mediated immunity in vivo, we administered 405 skin tests with two standard recall antigens (tetanus and Candida), 313 tetanus vaccines, and 375 pneumococcal vaccines, along with the collection of pre/post blood samples to measure antibody response, and 424 blood samples for complete blood count (CBC) laboratory testing. To evaluate lymphocyte cell sub-sites and cytokine expression following activation of peripheral blood T cells, the staff collected fresh blood specimens from 263 participants, which were express mailed to the University of California at Irvine (UCI) for analysis within 24 hours. To measure luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E), and progesterone (P), we collected 117 female and 236 male blood specimens, which were processed, frozen, and shipped in batches to the National Institute for Occupational Safety and Health (NIOSH) laboratory for analysis. Many of these analyses are still pending. To determine whether the women are ovulating normally, we obtained a month of daily urine specimens from 156 female participants, which were also frozen and shipped to NIOSH. We also collected 189 semen samples from male participants at licensed medical laboratories in Honolulu.

Future Activities:

During the project extension period, we will focus on final data collection of the enrolled participants and data verification. The final followup in data collection and data verification is particularly important for data quality control because of the complexities of the data collection procedures and the coordination of two project offices. We plan to devote a substantial effort toward verifying the tracking data, the study forms, and the data entered in the databases for future analyses.

Supplemental Keywords:

epidemiology, heptachlor, pesticide, reproductive function, immune function,, RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Toxics, Geographic Area, Genetics, Environmental Chemistry, Health Risk Assessment, Chemistry, pesticides, Endocrine Disruptors - Environmental Exposure & Risk, endocrine disruptors, Risk Assessments, Physical Processes, Children's Health, Endocrine Disruptors - Human Health, International, health effects, pesticide exposure, puberty, risk assessment, childhood development, vulnerability, age-related differences, endocrine disrupting chemicals, exposure, exposure studies, gene-environment interaction, environmental mutagens, fertility, human malformation, particle exposure models, gestational exposure, developmental biology, Oahu, Hawaii, human exposure, insecticides, susceptibility, toxicity, cumulative environmental exposure, lactational exposure, estrogen metabloism, endocrine disrupting chemcials, latent effects, diet, environmental stressors, environmental toxicant, harmful environmental agents, reproductive processes, toxic environmental contaminants, embryonic development, biological markers, endometriosis, growth & development, Heptachlor, developmental disorders, epidemiologic studies, exposure assessment

Progress and Final Reports:

Original Abstract
  • 2002 Progress Report
  • 2003 Progress Report
  • 2004 Progress Report
  • Final