We previously demonstrated that the frequency of birth defects among children of residents of the Red River Valley (RRV), Minnesota, USA, was significantly higher than in other major agricultural regions of the state during the years 1989-1991, with children born to male pesticide applicators having the highest risk. The present, smaller cross-sectional study of 695 families and 1,532 children, conducted during 1997-1998, provides a more detailed examination of reproductive health outcomes in farm families ascertained from parent-reported birth defects. In the present study, in the first year of life, the birth defect rate was 31.3 births per 1,000, with 83% of the total reported birth defects confirmed by medical records. Inclusion of children identified with birth or developmental disorders within the first 3 years of life and later led to a rate of 47.0 per 1,000 (72 children from 1,532 live births). Conceptions in spring resulted in significantly more children with birth defects than found in any other season (7.6 vs. 3.7%). Twelve families had more than one child with a birth defect (n = 28 children). Forty-two percent of the children from families with recurrent birth defects were conceived in spring, a significantly higher rate than that for any other season. Three families in the kinships defined contributed a first-degree relative other than a sibling with the same or similar birth defect, consistent with a Mendelian inheritance pattern. The remaining nine families did not follow a Mendelian inheritance pattern. The sex ratio of children with birth defects born to applicator families shows a male predominance (1.75 to 1) across specific pesticide class use and exposure categories exclusive of fungicides. In the fungicide exposure category, normal female births significantly exceed male births (1.25 to 1). Similarly, the proportion of male to female children with birth defects is significantly lower (0.57 to 1; p = 0.02). Adverse neurologic and neurobehavioral developmental effects clustered among the children born to applicators of the fumigant phosphine (odds ratio [OR] = 2.48; confidence interval [CI], 1.2-5.1). Use of the herbicide glyphosate yielded an OR of 3.6 (CI, 1.3-9.6) in the neurobehavioral category. Finally, these studies point out that (a) herbicides applied in the spring may be a factor in the birth defects observed and (b) fungicides can be a significant factor in the determination of sex of the children of the families of the RRV. Thus, two distinct classes of pesticides seem to have adverse effects on different reproductive outcomes. Biologically based confirmatory studies are needed.

Earlier studies by our group suggested the possibility that offspring of pesticide appliers might have increased risks of birth anomalies. To evaluate this hypothesis, 935 births to 34,772 state-licensed, private pesticide appliers in Minnesota occurring between 1989 and 1992 were linked to the Minnesota state birth registry containing 210,723 live births in this timeframe. The birth defect rate for all birth anomalies was significantly increased in children born to private appliers. Specific birth defect categories, circulatory/respiratory, urogenital, and musculoskeletal/integumental, showed significant increases. For the general population and for appliers, the birth anomaly rate differed by corp-growing region. Western Minnesota, a major wheat, sugar beet, and potato growing region, showed the highest rate of birth anomalies per/1000 live births: 30.0 for private appliers versus 26.9 for the general population of the same region. The lowest rates, 23.7/1000 for private appliers versus 18.3/1000 for the general population, occurred in noncorp regions. The highest frequency of use of chlorophenoxy herbicides and fungicides also occurred in western Minnesota. Births in the general population of western Minnesota showed a significant increase in birth anomalies in the same three birth anomaly categories as appliers and for central nervous system anomalies. This increase was most pronounced for infants conceived in the spring. The seasonal effect did not occur in other regions. The male/female sex ratio for the four birth anomaly categories of interest in areas of high phenoxy herbicide/fungicide use is 2.8 for appliers versus 1.5 for the general population of the same region (p = 0.05). In minimal use regions, this ratio is 2.1 for appliers versus 1.7 for the general population. The pattern of excess frequency of birth anomalies by pesticide use, season, and alteration of sex ratio suggests exposure-related effects in appliers and the general population of the crop-growing region of western Minnesota.Imagesp394-aFigure 1.Figure 2.

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In the current study, there was a modest but significant increase in risk (1.6- to 2-fold) for miscarriages and/or fetal loss occurring throughout the year in the spouses of applicators who use fungicides. There is a surprisingly significant deficit in the number of male children born to the spouses of fungicide applicators. First-trimester miscarriages occur most frequently in the spring, during the time when herbicides are applied. Use of sulfonylurea (odds ratio OR = 2.1), imidizolinone (OR = 2.6) containing herbicides, and the herbicide combination Cheyenne (OR = 2.9) by male applicators was statistically associated with increased miscarriage risk in the spring. Limited survey data from women who are the spouses of applicators did not show major alterations of long-term endocrinologic status (menarche, menopause, endometriosis). With regard to personal pesticide exposures, only women who engaged in pesticide application where there is direct exposure to these products are at demonstrable risk (OR = 1.8) for miscarriage. It was hypothesized that the overall reproductive toxicity observed in this population is, for the greater part, a male-mediated event. Clarification of exposure events leading to reproductive toxicity through direct measurements of exposure in both men and women is needed to resolve this issue.

In preparation for a human study of worker exposure to grain fumigants and pesticides, we decided to screen commonly used fumigants for genotoxic effects in vitro. This research strategy was employed to test the possibility that structurally simple chemicals might have similar genotoxic properties in vivo and in vitro. As a first step, we designed our in vitro protocol to mimic to the extent possible, a single in vivo exposure of lymphocytes to fumigants. Go lymphocytes were treated with different doses of carbon tetrachloride, carbon disulfide, methyl bromide, chloropicrin, and melathion with and without addition of rat liver homogenate for 1/2 hour, washed free of toxicant, and stimulated with PHA. After culture, the prepared slides were studied for chromosome aberrations and SCEs. Malathion, methyl bromide, and chloropicrin significantly induced SCEs without S-9. Carbon disulfide alone required S-9 for significant SCE induction. Chromosome aberrations were significantly increased by malathion and methyl bromide. Carbon tetrachloride failed to induce SCEs or chromosome aberrations with or without S-9. We concluded from these preliminary studies and other comparable work that the fumigants studied here may be less likely to express genotoxicity in terms of SCEs or chromosome aberrations than ethylene oxide or phosphine given a single short-term in vivo exposure. The final design of our human study was altered to focus on seasonal worker exposure rather than on a single exposure event.