2003 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: Glenn, Barbara
Project Period: March 1, 2002 through February 28, 2005 (Extended to August 31, 2006)
Project Period Covered by this Report: March 1, 2003 through February 28, 2004
Project Amount: $1,931,310
RFA: Endocrine Disruptors: Epidemiologic Approaches (2001) RFA Text |  Recipients Lists
Research Category: Health , Safer Chemicals , Endocrine Disruptors


The objective of this research project is to determine whether gestational exposure to the cyclodiene insecticide, heptachlor, permanently alters reproductive and immune function. The research project 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). This resulted in gestational exposure to offspring of women who drank cows’ milk during that period. The study is using a population of young adults, born between July 1981 and June 1982, who participated in an earlier study of the neurobehavioral effects of heptachlor epoxide exposure. The study population will include 400 young adults who were in utero on Oahu at the time of the milk contamination and 200 unexposed comparison participants, matched for age and ethnicity.

The study will assess sensitive biological indicators of reproductive and immune function, including: serum reproductive hormone concentrations to include 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 pneumoccal vaccine; and the proportion of Th1 and Th2 type CD4+ cell subsets in the peripheral blood. Susceptibility of peripheral blood T cells to activation-induced cell death will be assessed using in vitro analysis of Fas (CD95) and its ligand (CD95L) expression, and the percentage of apoptotic T cells will be assessed with Annexin V staining, at basal level and following activation.

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:

Activities during Year 2 of the project, focused on continuing tracing and recruitment of potential participants and data collection of eligible participants. As of February 2004, the staff was able to contact or finalize tracing 865 persons, with 101 participants still being traced. Of the 865 persons, the staff halted the tracing of 270 potential participants who were not reachable after multiple attempts of direct mailings, telephone calls, visits to the last known address, and Internet address searches. Among the 595 participants who were contacted, 184 participants were enrolled and participated in the project, 136 declined to take part in the study (74% with unknown eligibility status), 120 were not eligible (87 were on birth control, 33 with health conditions), 49 were not available (off-island with no plan to return), and 55 were lost between initial contact and enrollment. The rest are to be enrolled in the study.

Tracing and recruiting potential participants has been difficult for the project staff because of three primary reasons. First, the potential study population is an actively mobile age group. They graduated from high school a few years ago and many left Oahu to go to college or find jobs. Also, many of their families have moved, so the address available from the previous study is no longer valid. Second, many of the young adults in the potential study population do not have permanent addresses and landline telephones, so it is difficult to trace them using standard tracing methods. Third, as anticipated for this age group, a large proportion of the females are not eligible because they are using hormonal contraceptive methods. In addition to multiple phone calls, the project staff have used the following strategies to improve the recruitment rate: direct mailing of the project brochures with a personal letter, checking addresses using the Web and phonebooks, sending emails, and conducting home visits.

Participant enrollment and data collection began during Year 2 of the project. As of February 2004, the staff had enrolled and begun data collection on 184 participants (111 males and 73 females). Of these, the staff completed data collection on 82 participants, 4 dropped out of the study, and 18 moved off of the island. Data collection continues on the rest of the participants. Some of the tests completed include vaccination of participants (n=116), anergy skin tests (184), semen reports (76), daily urine collection for menstrual cycle (60), serum hormone specimens (159), and CBC and fresh blood specimen for immune testing (173).

Future Activities:

The project staff will continue to trace up to 1,800 participants from the earlier neurobehavioral study to determine eligibility and willingness to participate in this research project. If needed to reach the target number of 600 participants, the project will expand the sampling frame by recontacting schools on Oahu to identify age-eligible graduates of the schools.

The field data collection will continue until the target number of participants is reached. The project staff will conduct and coordinate the data collection. Biological specimens are shipped to the analytical laboratories. The tetanus and pneumococcal antibody titers and semen specimens are being analyzed at a licensed medical laboratory in Hawaii; the reproductive serum and urine specimens are being analyzed at a National Institute for Occupational Safety and Health laboratory in Cincinnati, Ohio; and the immune function assays are being performed at the University of California-Irvine. Data management and analysis will be conducted at the University of California-Irvine.

Supplemental Keywords:

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

Progress and Final Reports:

Original Abstract
2002 Progress Report
2004 Progress Report
2005 Progress Report
2006 Progress Report