2004 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, 2004 through February 28, 2005
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:

The project staff continued to trace and recruit participants to enroll in the project during year 3. As of February 2005, the project staff attempted to trace 1,300 potential participants from the sampling frame of participants in the earlier neurobehavioral study. Among the participants who were contacted, 299 participants were enrolled and participated in the project, 192 refused to take part in the study, 241 were not eligible (on birth control or with health conditions), 281 participants were not reachable through direct mailings and phone calls, 8 were pending to be enrolled, and 13 were lost to recruitment after being contacted. The rest (591 potential participants) were in the process of being contacted.

Participant tracing and recruitment has been difficult for several reasons. First, the potential study participants graduated from high school about 4 to 6 years ago, and many of them have left Hawaii to attend college or find jobs on the Mainland or neighboring islands with no plans to return. Second, the contact list used to trace potential participants was generated about 7 years ago, so many of their families have moved and become untraceable. Third, a large proportion of the females are not eligible for the study because they were using hormonal methods of contraception.

As of February 2005, the total number of participants for the study was 299, of whom 164 were male and 135 were female. We collected 299 participant questionnaires and 201 parent questionnaires. To evaluate the integrity of cell-mediated immunity in vivo, we administered 249 skin tests with two standard recall antigens (tetanus and Candida), 189 tetanus vaccines, and 225 multivalent pneumococcal vaccines, along with the collection of pre/post blood samples to measure antibody response and 265 blood samples for complete blood count (CBC) laboratory testing. To evaluate lymphocyte cell subtypes and cytokine expression following activation of peripheral blood T cells, the staff collected fresh blood samples for 263 participants, which were express mailed to the University of California at Irvine (UCI) for delivery and analysis within 24 hours of the blood draw. To measure luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E), and progesterone (P), we collected 59 female blood samples and 152 male blood specimens, which were processed, frozen, and shipped in batches to the National Institute for Occupational Safety and Health (NIOSH) for analysis. To determine whether the women are ovulating normally and have normal luteal phase function (by measuring LH, E3G, and P3G), we collected a month of daily urine specimens from 94 females. In addition, we collected 118 semen specimens at a licensed medical laboratory to assess semen quality among male participants.

Future Activities:

The study will continue to trace, recruit, and study participants from the original sampling frame. While implementing the field work, we also have been considering strategies for future activities in the area of participant recruitment during the coming project year. The first strategy is to consider using a commercial people search company or credit agency to assist with tracing participants who cannot be located by the project staff using available techniques. The second strategy is to contact participating and non-participating high schools of the previous study. We have made attempts to obtain assistance from these schools and the Hawaii Department of Education to select a list of past students who meet the birth date specifications and to send them an information letter about the study. We also contacted the ongoing Hawaii Health Survey to see if we could identify age-eligible subjects through this random population survey. However, based on initial modeling, we found that the yield would be too low to justify the cost of this approach.

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
  • 2005 Progress Report
  • Final