TABLE 9-3Selected Epidemiologic Studies—Female Fertility (Altered Hormone Concentrations, Subfertility, or Infertility)

Study PopulationExposed CasesaExposure of Interest/Estimated Relative Risk (95% CI)aReference
OCCUPATIONAL—HERBICIDE-USING
WORKERS (not related to IARC sprayer cohorts)
UNITED STATES
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; followups with CATIs 1999–2003 and 2005–2010 Phenoxy herbicides 
8,038 premenopausal women age 30–55 at enrollment  Farr et al., 2006
Pesticide exposure5,0130.9 (0.8–1.0) 
Herbicide exposure3,7250.9 (0.7–1.1) 
Phenoxy herbicide exposure1,3790.9 (0.7–1.1) 
Menstrual-cycle characteristics of 3,103 premenopausal women age 21–40  Farr et al., 2004
Reported at enrollment had used herbicides1,291  
Short menstrual cycle 0.6 (0.4–1.0) 
Long menstrual cycle 1.0 (0.5–2.0) 
Irregular 0.6 (0.3–0.9) 
Missed period 1.4 (1.0–2.0) 
Intermenstrual bleeding 1.1 (0.8–1.7) 
ENVIRONMENTAL
Seveso (Italy) Women's Health Study—Industrial accident July 10, 1976; 981 women between infancy and 40 yrs of age at the time of the accident, who resided in Zones A and B TCDD 
Time to pregnancy and infertility in women from Zones A and B who attempted pregnancy after 1976  Eskenazi et al., 2010
20-yr followup to 1996—men and women
Time to pregnancy (adjusted fecundability OR)
Log10 TCDD2780.8 (0.6–1.0) 
Categorical TCDD (ppt)
≤ 20521.0 (reference) 
20.1–44.4760.8 (0.5–1.3) 
44.5–100750.7 (0.5–1.1) 
> 100750.6 (0.4–1.0) 
Infertility (adjusted OR)
Log10 TCDD491.9 (1.1–3.2) 
Categorical TCDD (ppt)
≤ 2061.0 (reference) 
20.1–44.491.1 (0.4–3.6) 
44.5–100162.5 (0.8–7.3) 
> 100182.8 (1.0–8.1) 
Fibroids among women from Zones A and B who were newborn to age 40 in 1976  Eskenazi et al., 2007
Uterine fibroids (age-adjusted HR)
Log10 TCDD (ppt)2510.8 (0.7–1.1) 
Categorical TCDD (ppt)
≤ 20621.0 (reference) 
20.1–75.01100.6 (0.4–0.8) 
> 75790.6 (0.4–0.9) 
Ovarian function in women from Zones A and B who were newborn to age 40 in 1976; results are for a 10-fold increase in serum TCDD  Warner at al., 2007
Ovarian follicles (age-adjusted OR):
in follicular phase651.0 (0.4–2.2) 
Ovulation (age-adjusted OR):
in luteal phase871.0 (0.5–1.9) 
in midluteal phase551.0 (0.4–2.7) 
Estradiol (age-adjusted ß): slopes for Log10 
  TCDD 
in luteal phase87−1.8 (−10.4–6.8) 
in midluteal phase55−3.1 (−14.1–7.8) 
Progesterone (age-adjusted ß):
in luteal phase87−0.7 (−2.4–1.0) 
in midluteal phase55−0.8 (−3.7–2.0) 
Age at menopause in women from Zones A and B who were newborn to age 40 in 1976  Eskenazi et al., 2005
Onset of natural menopause (unadjusted HR)
Log10 TCDD1691.0 (0.8–1.3) 
Menopause category Serum TCDD median (IQR) 
Premenopause26043.6 (0.2–0.9) 
Natural menopause16945.8 (0.3–1.0) 
Surgical menopause8343.4 (0.3–1.0) 
Impending menopause1343.8 (0.2–1.1) 
Perimenopause3336.5 (0.2–0.9) 
Other5839.6 (0.2–0.9) 
Age at menarche in women from Zones A and B who were premenarcheal in 19762821.0 (0.8–1.1)Warner et al., 2004
All premenarcheal women in 1976 (unadjusted HR)
Log10 TCDD2821.0 (0.8–1.1) 
Women < 8 yrs in 1976 (unadjusted HR)
Log10 TCDD1581.1 (0.9–1.3) 
Menstrual-cycle characteristics in women from Zones A and B who were premenopausal, less than age 44, and not recently pregnant, breastfeeding, or using hormonal medications  Eskenazi et al., 2002b
Menstrual-cycle length (adjusted ß)
Log10 TCDD2770.4 (−0.1–0.9) 
Premenarcheal at explosion 0.9 (0.0–1.9) 
Postmenarcheal at explosion 0.0 (−0.6–0.5) 
Days of menstrual flow (adjusted ß)
Log10 TCDD3010.2 (−0.1–0.4) 
Premenarcheal at explosion 0.2 (−0.2–0.5) 
Postmenarcheal at explosion 0.2 (−0.2–0.5) 
Heaviness of flow (scanty vs moderate/heavy;
adjusted OR)
Log10 TCDD300.8 (0.4–1.6) 
Premenarcheal at explosion 0.3 (0.1–1.1) 
Postmenarcheal at explosion 1.4 (0.7–2.6) 
Irregular cycle (vs regular; adjusted OR)
Log10 TCDD240.5 (0.2–1.0) 
Premenarcheal at explosion 0.5 (0.2–1.4) 
Postmenarcheal at explosion 0.4 (0.2–1.2) 
Other International Environmental Studies
Taiwanese pregnant women (18–40 yrs of age); placental TEQ concentrations of TCDDs, TCDFs, PCBs Dioxin/Regression adjusted for maternal age,Chao et al., 2007
  BMI, parity 
≥ 18 yrs old, “regular menstrual cycle”
Dioxin TEQ p = 0.032 
PCB TEQ p = 0.077 
Women with “longest menstrual cycle”
Dioxin TEQ p = 0.269 
PCB TEQ p = 0.006 
CASE-CONTROL STUDIES
US Case-Control Studies
Women in Wisconsin with or without infertility (maternal exposure)—incidence Phenoxy herbicidesGreenlee et al., 2003
Mixed or applied herbicides212.3 (0.9–6.1) 
Used 2,4,5-T99 cases (2.7%) 11 controls (3.4%) 
Used 2,4-D44 cases (1.2%) 
  4 controls (1.2%) 

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; BMI, body mass index; CATI, computer-assisted telephone interviewing; CI, confidence interval; HR, hazard ratio; IARC, International Agency for Research on Cancer; IQR, inter-quartile range; OR, odds ratio; PCB, polychlorinated biphenyl; ppt, parts per trillion; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDF, tetrachlorodibenzofuran; TEQ, (total) toxic equivalent.

a

Given when available; results other than estimated risk explained individually.

From: 9, Fertility and Gestational Outcomes

Cover of Veterans and Agent Orange
Veterans and Agent Orange: Update 2012.
Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Ninth Biennial Update); Board on the Health of Select Populations; Institute of Medicine.
Washington (DC): National Academies Press (US); 2014 Mar 6.
Copyright 2014 by the National Academy of Sciences. All rights reserved.

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