2002 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, 2002 through February 28, 2003
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 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 (1981-82), resulting 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 this 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:

  1. serum reproductive hormone concentrations (testosterone in men, estradiol and progesterone in women, and luteinizing hormone and follicle-stimulating hormone in both men and women);
  2. semen samples in men;
  3. 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 expression analysis of Fas (CD95) and its ligand (CD95L) and the percentage of apoptotic T cells stained with Annexin V 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 1 of the project focused on the following areas:

  1. administrative and logistical preparations for the field study;
  2. participant tracing and recruitment;
  3. and changing project implementation for vaccinations and skin tests.

The original timeline for administrative and logistical preparation and participant tracing and recruitment was extended for 6 months because of difficulty in recruiting the project staff in Hawaii and complications with a sub-contract for administering some of the biological tests, which required a change in the protocol. Field data collection began at the end of the first project year.

Preparations for the field study included the following activities:

  1. establishing subcontracts for the field operations in Hawaii;
  2. establishing a project office;
  3. recruiting and training project staff;
  4. coordinating logistics with various laboratories;
  5. and developing final procedures and study forms.

From August 2002 to February 2003, the project staff attempted tracing and recruitment of 679 potential participants from the sampling frame of participants in the earlier neurobehavioral study. As of February 2003, the staff was able to contact 460 persons. Among the contacted participants, 67 had moved to other states or Neighbor Islands, and 393 were on Oahu. Among those who were on Oahu, 198 participants were eligible and willing to take part in the study; 86 refused, 98 were not eligible (including 82 on contraceptives), and 11 were unsure. The eligible subjects were enrolled into the study.

During the year, we revised the study plan to use a clinical research center in Hawaii to administer the vaccinations and skin tests, rather than using a project nurse. This change was needed because of medical-legal issues related to the contracted clinical fieldwork in Hawaii. This administrative change delayed implementation of the fieldwork for about 3 months.

Future Activities:

The project staff will continue to trace up to 1,800 participants from the earlier neurobehavioral study to determine current eligibility and willingness to participate in this study. A commercial searching service will be used to trace difficult to reach subjects. If needed to reach the target number of 600 participants, the study will expand the sampling frame by re-contacting 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, which is anticipated to take approximately 30 months. The project staff conducts and coordinates 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, endocrine disruption, toxics, risk assessments, cumulative environmental exposure, development biology, embryonic development, endocrine disrupting chemicals, environmental mutagens, gestational exposure, pesticide exposure, toxic environmental contaminants,, 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
  • 2003 Progress Report
  • 2004 Progress Report
  • 2005 Progress Report
  • Final