Project Number: 9278287 Project Title: Methods to Evaluate Reproductive Potential of Women Division: DART Project Officer (PO): James S. Kesner PO Degree: Ph.D. PO Area of Expertise (scientific discipline): Reproductive Biology Project Start Date: 10/87 Project End Date: 09/06 Total Budget over the Project Period: $302,682 Goal/Sub-Goal: Chronic Effects of Pesticide Exposure Health Outcomes Research Challenge/Issue: An ever-increasing number and variety of chemicals are used in agriculture which are known to be reproductive toxicants and endocrine disrtuptors. A prime example of these chemicals that pose great risk in agriculture are the many varied pesticides and the chemicals added to their formulations. Agriculture workers, their families, and the surrounding communities are at risk of exposure to these chemicals. In addition to the adult agricultural workers, 2.6 million teenagers were employed on the farm in 1995. Agricultural workers and their families are at risk of direct exposure to these chemicals. In addition, agricultural workers, their families, and those who comprise the agricultural community may be exposed through the air, soil, food, or water, or through contamination brought home by the agriculture worker, e.g., on their clothes. Activities: The problem and challenge were defined from a large literature and from collaborators expert in the field(s) of toxicity, exposure, and outcomes. The studies have been approved by peerreviews and, in most cases, feedback from stakeholders and exposed populations obtained by the respective collaborators. Study populations include: 1) young adult men and women in Hawaii exposed to a heptachlor in utero or during breast feeding; 2) agriculture community in Illinois drinking ground water with high levels of atrazine; 3) pesticide applicators in Minnesota & Iowa; 4) subsistence Native American community exposed to DDT in their soil, water, and food. Studies conducted previously or currently by the Team assess a wide spectrum of reproductive health outcomes including: reproductive endocrine status, menstrual cycle and ovulatory function and prostate cancer. Exposures studied include mix of pesticides, specific pesticides (e.g., 2,4-D, DDT, heptachlor, atrazine), and pesticide adjuvants. Collaborators: Dean Baker & Ulrike Luderer, University of California/Irvine; John Reif & Lori Cragin, Colorado State University; Elaine Smith, Univeristy of Iowa; Vincent Garry, University of Minnesota; Bruce Wainman, McMaster University; Leonard Tsuji, University of Waterloo. Stakeholders:
While not always overtly expressing their needs or interest, stakeholders for this program fit into three categories: 1) agricultural workers, their families, and the communities impacted by pesticides and other agricultural chemicals that threaten reproductive health, 2) researchers who use the methods & models developed by RHAT/DART within this research program, and 3) agencies that will use the information derived from this research program (e.g., NIH, U.S. & state EPAs, NTP, NIOSH). Outputs: Methods Developed: Several methods have been developed, at least in part, to study the impact of occupational hazards on reproductive health of agricultural workers. These methods include: 1) demonstrate the superiority of an LH immunoassay to reliably measure the preovulatory surge in urine; 2) an algorithm for detecting features of the hormone profiles of the human menstrual cycle; 3) endocrine markers of ovulation and of nonconceptous mentrual cycles; and 4) a method to measure urinary creatinine measurement using multilayer dry film reagent technology. Assessing Reproductive Health Effects of Chemicals in Agriculture:??? Significant findings from population studies: 1) hand-held, backpack sprayer is the applicator method associated with highest urinary 2,4-D levels in men, while high urinary 2,4-D levels are associated with altered luteinizing hormone, follicle stimulating hormone, and testosterone levels and altered genomic stability (measured by V(D) J rearrangement frequency), which appears reversible; 2) pesticide adjuvants exhibited positive dose-response for in vitro genotoxicity effects; 3) preliminary data reveal that serum DDT levels in subsistence Native American women are directly correlated with follicular phase LH levels and inversely correlated with luteal phase FSH levels. Publications in refereed scientific journals: Baird DD, Weinberg CR, Zhou H, Kamel F, McConnaughey DR, Kesner JS, Wilcox AJ. Preimplantation urinary hormone profiles and the probability of conception in healthy women. Fertil Steril 71:40-49, 1999 Dunson DB, Weinberg CR, Baird DD, Kesner JS, Wilcox, AJ. Assessing human fertility using several markers of ovulation. Stat Med 20:965-78, 2001 Garry VF, Burroughs B, Tarone R, Kesner JS. Herbicides and adjuvants: an evolving view. Toxicol and Ind Health 15: 159-167, 1999 Garry VF, Tarone RE, Kirsch IR, Abdallah JM, Lombardi DP, Long LK, Burroughs BL, Barr DB, Kesner JS. Biomarker correlations of urinary 2,4-D levels in foresters: genomic instability and endocrine disruption. Environ Health Perspect 109:495-500, 2001 Kesner JS, Knecht EA, Krieg EF Jr, Wilcox AJ, O'Connor JF. Detecting preovulatory luteinizing hormone surges in urine. Human Reprod 13: 15-21, 1998 Kesner JS, Knecht EA, Krieg EF Jr. Measuring endocrine profiles of women in field studies. Scand J Work Environ Health 25 Suppl 1: 17-19, 1999
Kesner JS, Knecht EA, Krieg EF Jr. Assessing the Endocrine Effects of Occupational Exposures on Menstrual Cycle Function. In: Izmerov NF, Zaitseva NV, May IV, Shur PZ, Brazhkin AV, Khoroshavin VA (eds) Environmental Health. Russian Health Ministry Scientific & Development Centre for Environmental Safety, Perm, Russia, pp 194-197 [85-88], 2003 Krieg EF Jr, Kesner JS, Knecht EA. An algorithm for detecting features of the hormone profiles of the human menstrual cycle. Computers in Biol Med 29:229-242, 1999 Scialli AR, Swan SH, Amler RW, Baird DD, Eskenazi B, Gist G, Hatch MC, Kesner JS, Lemasters GK, Marcus M, Paul ME, Schulte P, Taylor Z, Wilcox AJ, Zahniser C. Assessment of reproductive disorders and birth defects in communities near hazardous chemical sites. II. Female reproductive disorders. Reprod Toxicol 11: 231-242, 1997 Documents prepared to inform and educate worker populations: Kesner JS, Lynch DD, Schnorr TM, Schrader SM, Wess JA. The Effects of Workplace Hazards on Female Reproductive Health - DHHS (NIOSH) Publication No. 99-104, 1999 Document prepared to solicit partners and to alert stakeholders: Schrader SM, Kesner JS. Reproductive Health: Developing Partnerships in the Study of Reproductive Hazards in the Workplace. DHHS (NIOSH) Publication No. 2002-152, 2002 Thesis: Menstrual Cycle Characteristics and Reproductive Patterns in Women Exposed to Atrazine in Drinking Water. Thesis for the Degree of Ph.D. for Lori Ann Cragin from Colorado State University - In Progress Abstracts: Cragin L, Kesner J, Barr D, Bachand A, Meadows J, Reif J. Menstrual cycle characteristics and reproductive patterns in women exposed to atrazine in drinking water. International Conference on Environmental Epidemiology and Exposure. September 2-6, 2006, Paris, France Doswell WM, Kesner JS, Knecht EA. Urine endocrine measurements during female pubertal onset. Society for Research on Adolescence, 1998 Kesner JS, Knecht EA, Krieg EF Jr. Measuring endocrine profiles of women in field studies. International Symposium on Environment, Lifestyle & Fertility, Aarhus, Denmark, December 9, 1997 Kesner JS. Evaluating the effects of occupational hazards on the reproductive health of women. 10th Annual Meeting of the Allegheny-Erie Regional Chapter of the Society of Toxicology, Pittsburgh, PA, May 15, 1998 Kesner JS. Evaluating the effects of occupational hazards on the reproductive health of women. Indiana American Industrial Hygiene Association Conference, Indianapolis, IN, September 13, 1999.
Kesner JS, Knecht EA, Krieg EF Jr. Assessing the Endocrine Effects of Occupational Exposures on Menstrual Cycle Function. International Conference on Environment and Health, May 13-18, 2003, Perm, Russia. Kesner JS. Biological evaluation of menstrual cycle function in women exposed to occupational and environmental hazards. International Congress on the Prevention of Occupational and Environmental Disorders of Reproductive Health, June 30, 2004, Volgograd, Russia. Abstract. Knecht EA, Krieg EF Jr, Clark JC, Kesner JS. Urinary creatinine measurement using a Vitros 250 chemistry analyzer compared with the Jaffe method. 54th Annual Meeting of the American Association for Clinical Chemistry, July 30, 2002, Orlando, FL, Clin Chem 48:A55, 2002. Wainman B, Tsuji L, Nieboer E, Kesner J, Weber J-P, Vasquez R. The effects of persistent organic pollutants (POPs) and toxic metals (TMs) on menstrual cycle function in the Cree of Western James Bay, Canada. International Federation of Fertility Societies 18th World Congress on Fertility & Sterility. May 23-28, 2004, Montreal, Canada. Abstract. Intermediate Outcomes: 1) Peer-reviewed publications from the program are frequently cited. For example, this laboratory's publications are often cited as a reliable method to measure the preovulatory LH surge in urine. 2) The researchers within the program are sought out nationally and internationally to provide technical assistance and expertise to study occupational reproductive health issues. Typically, these requests are accompanied by external funding for the Program. 3) Methods developed within the program are continually being updated and are used by other researchers. 4) A commercial diagnostics company (PerkinElmer) adapted two immunoassays developed by the program for manufacture and sales. 5) Based on preliminary results, Canadian Institutes of Health Research is funding a full-scale study of reproductive health of women living in a subsistence Native American community exposed to DDT. 6) A study of pesticide applicators in Minnesota is thought to have been inspired by research done by this Program. 7) In cases where exposures and adverse reproductive effects are identified, exposures will be reduced through education, and, if necessary, through regulation. 8) Health effects data from workers can be used for risk assessments and for the development of recommended exposure levels. End Outcomes: None available at this time due to the ongoing status of the studies. External Factors: There were no remarkable external factors that unusually affected the success of the program, aside from normal hurdles of conducting human population studies in the workplace. Future Directions: The number and variety of chemicals used in agriculture continue to increase, providing a challenge to prioritize and assess the rrproductive toxicity of them in humans. Advances in our understanding of the toxicity of endocrine disruptors highlight the threat of many agricultural
chemicals. New methods continue to be needed to provide reserachers with state-of-the-art biological markers of reproductive health. As indicated in describing Emerging Problems, much research remains to be conducted. The Program has several on-going collaborative studies.