Veterans and Agent Orange Update 2000 (2001) / Chapter Skim
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8 Reproductive Effects
8 Reproductive Effects
Pages 399-439
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From page 399... ...
The literature includes papers describing environmental, occupational, and Vietnam veteran studies that evaluated herbicide exposure and the risk of adverse outcomes, including spontaneous abortion, birth defects, stillbirths, neonatal and infant mortality, childhood cancer, low birthweight, and sperm quality and infertility. Besides studies of herbicides and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
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From page 400... ...
The following specific categories of reproductive effects have been reviewed in previous Veterans and Agent Orange (VAO) reports (IOM, 1994, 1996, 1999~: fertility, sex ratio, spontaneous abortion, stillbirth and infant mortality, low birthweight and preterm delivery, and birth defects.
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From page 401... ...
Interviews were conducted with parents of the cases and controls by telephone where possible and inperson otherwise. The questions covered potential confounders and activities that would involve potential exposure to pesticides.
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From page 402... ...
No verification had been conducted for those responding that their children had no defects. In the pre-Southeast Asia period, those in the Ranch Hand group had a lower percentage of children with birth defects than the comparison group (OR = 0.7~.
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From page 403... ...
Research on chemical production workers with TCDD exposure suggests that some hormonal changes are associated with such exposure, but it is unclear whether these changes could be responsible for an increase in spine bifida or other birth defects. A summary of the biologic plausibility for the reproductive effects of TCDD and the herbicides in general is presented in the conclusion to this chapter.
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From page 404... ...
50 1.5 (NR) Neural tube defects among Ranch Hands childrend Neural tube defects among comparison children Vietnam Experience Study Spina bifida among Vietnam veterans' children Spina bifida among non-Vietnam veterans' children Anencephaly among Vietnam veterans' children Anencephaly among non-Vietnam veterans' children 4 o 9 1.7 (0.6-5.0)
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From page 405... ...
d Four neural tube defects among Ranch Hand offspring include two spine bifida (high dioxin level) , one spine bifida (low dioxin)
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From page 406... ...
(2000) also report on fecundability, in an investigation of female greenhouse workers in Denmark.
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From page 407... ...
However, data on specific pesticide exposures or on TCDD contamination of such pesticides were not available. Conclusions Strength of Evidence in Epidemiologic Studies There is no information contained in the research reviewed for this report to change the conclusion that there is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides (2,4-D, 2,4,5T and its contaminant TCDD, cacodylic acid, and picloram)
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From page 408... ...
120-1,999 2,000-3,999 4,000-9,999 210,000 Studies Reviewed in Update 1996 Henriksen et al., 1996 Ranch Hands Low testosterone High dioxin (1992) High dioxin (1987)
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From page 409... ...
Major types of study designs include cohorts of women asked retrospectively about their pregnancy history, cohorts of pregnant women, usually those receiving prenatal care, and cohorts of women who are monitored for future pregnancies. Retrospective reports may be limited by memory loss, particularly of spontaneous abortions that took place a long time before.
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From page 410... ...
When analyses were conducted for specific work exposures and adjusted for maternal age, self-reported strenuous work, smoking, and alcohol consumption, use of herbicides was associated with anincreased risk of spontaneous abortion, OR = 2.0 (1.1-3.5~. The primary weaknesses of this study were the low response rate with consequent possible selection bias and the lack of information regarding specific herbicides used.
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From page 411... ...
Increased Risk of Disease Among Vietnam Veterans Few studies have addressed spontaneous abortion in Vietnam veterans. The recent doctoral dissertation examining female veterans provides weak evi
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From page 412... ...
Summary of VAO, Update 1996, and Update 1998 The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to the herbicides used in Vietnam or the contaminant dioxin and stillbirth, neonatal death, and infant death. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding.
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From page 413... ...
A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3. Increased Risk of Disease Among Vietnam Veterans Given the large uncertainties that remain about the magnitude of potential risk of stillbirth, neonatal death, and infant death, it is not possible for the committee to quantify the degree of risk likely to be experienced by Vietnam veterans because of their exposure to herbicides in Vietnam.
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From page 414... ...
; low SES; previous low birthweight or preterm birth; multiple gestations; cigarette smoking; and cervical, uterine, or placental abnormalities (Berkowitz and Papiernik, 1993~. Summary of VAO, Update 1996, and Update 1998 The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to the herbicides used in Vietnam or the contaminant dioxin and low birthweight.
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From page 415... ...
(1998) conducted a study of low birthweight among children whose fathers were fishermen.
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From page 416... ...
Conclusions Strength of Evidence in Epidemiologic Studies There is no information contained in the research reviewed for this report to change the conclusion that there is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides (2,4-D, 2,4,5T and its contaminant TCDD, cacodylic acid, and picloram) and either low birthweight or preterm birth.
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From page 417... ...
CHILDHOOD CANCERS Background The American Cancer Society (ACS) estimates that approximately 8,600 children under the age of 15 will be diagnosed with cancer in the United States in 2001.
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From page 418... ...
Update of Scientific Literature Occupational Studies An earlier study, not previously summarized in Veterans and Agent Orange reports, examined occupational herbicide exposures in relation to acute myelogenous leukemia (Buckley et al., 1989~. This study was assembled by the Children's Cancer Study Group and included cases diagnosed from 1980 to 1984.
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From page 419... ...
(1999) examined the risk of childhood acute lymphocytic leukemia associated with pesticide use: 491 cases in 0-9-year-old children were identified from tertiary care centers in the province of Quebec, Canada, over the years 1980-1993.
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From page 420... ...
. A much larger population-based case-control interview study of several childhood cancers was conducted in West Germany by Meinert et al.
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From page 421... ...
It is believed that childhood cancers at very young ages are more likely to be etiologically related to preconception or in utero exposures than those diagnosed at later ages. Limitations of the study include possible residual confounding from not having detailed exposure data on smoking and marijuana use; the unexplained stronger association with increasing interval between service and conception; and possible other factors associated with service in Vietnam or Cambodia, including postwar exposures.
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From page 422... ...
Synthesis No firm evidence links exposures to the herbicides used in Vietnam with most childhood cancers, including acute lymphocytic leukemia, chronic leukemias, non-Hodgkin's lymphoma, brain tumors, neuroblastoma, and cancers at other sites. A cohort study reports a slight elevation in risk to children of sawmill workers (Heacock et al., 2000)
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From page 423... ...
Three studies provide evidence regarding an association between exposure to the herbicides used in Vietnam and acute myelogenous leukemia in the children of veterans. The first is a case-control study of AML and parental occupational exposures conducted by the Children's Cancer Study Group (Buckley et al., 1989~.
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From page 424... ...
This is a change in classification from previous Veterans and Agent Orange reports, which found inadequate/insufficient evidence to determine whether an association existed for AML and other cancers. When the whole of the literature was considered, the committee found that it met the definition established for limited/suggestive evidence that is, evidence is suggestive of an association between herbicides and the outcome, but limited because chance, bias, and confounding could not be ruled out with confidence.
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From page 425... ...
There is inadequate or insufficient evidence to determine whether an association exists between exposure to the herbicides considered in this report or the contaminant dioxin and most childhood cancers, including acute Iymphocytic leukemia, chronic leukemias, non-Hodgkin's Iymphoma, brain tumors, neuroblastoma, and cancers at other sites. Although two moderately sized investigations did observe associations with ALL, all leukemia, or nonHodgkin's lymphoma in children, these studies were still problematic, because of reliance on self-reports for exposure assessment and/or a lack of information on exposures prior to the child's conception, the time period relevant for cancer among children of Vietnam veterans.
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From page 426... ...
For these reasons, it is not possible for the committee to quantify the degree of risk for AML likely to be experienced by the children of Vietnam veterans because of their fathers' exposure to herbicides in Vietnam. There remains insufficient information to quantify the degree of risk for other childhood cancers in the children of veterans resulting from their fathers' exposures to herbicides in Vietnam.
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From page 427... ...
REPRODUCTIVE EFFECTS TABLE 8-3 Selected Epidemiologic Studies Childhood Cancers 427 Reference Study Population Exposed Cases RR, OR, or SIR (95% CI) OCCUPATIONAL STUDIES Heacock et al., 2000 Cohort of sawmill workers' offspring; exposure via fungicides contaminated with PCDDs and PCDFs Leukemia, all workers Brain cancer, all workers Leukemia, high chlorophenate exposure 5 Brain cancer, high chlorophenate exposure 5 Buckley et al., 1989 Children's Cancer Study Group—casecontrol study of children of parents exposed to pesticides or weed killers AML in children with any paternal exposure AML in children with paternal exposure >1,000 days AML in children with maternal exposure >1,000 days ENVIRONMENTAL STUDIES New Studies Meinert et al., 2000 Population-based case-control study of childhood cancer Leukemias, paternal exposure, year before pregnancy Leukemias, paternal exposure, during pregnancy Lymphomas, paternal exposure, year before pregnancy Lymphomas, paternal exposure, during pregnancy Leukemias, maternal exposure, year before pregnancy Leukemias, maternal exposure, during pregnancy Lymphomas, maternal exposure, year before pregnancy Lymphomas, maternal exposure, during pregnancy SIR = 1.0 (0.5-1.8)
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From page 428... ...
428 TABLE 8-3 Continued VETERANS AND AGENT ORANGE: UPDATE2000 Reference Study Population RR, OR, Exposed or SIR Cases (95% CI) Pearce and Parker, 2000 Infante-Rivard et al., 1999 Cohort study examining paternal occupation on death certificate of children who died of kidney cancer Paternal agricultural occupation Population-based case-control study of childhood ALL and household herbicide use during pregnancy Studies Reviewed in Update 1996 Pesatori et al., 1993 Seveso residents aged 0-19 years—10-year follow-up, morbidity All cancers Ovary and uterine adnexa Brain Thyroid Hodgkin's lymphoma Lymphatic leukemia Myeloid leukemia Bertazzi et al., 1992 VIETNAM VETERANS New Studies AIHW, 2000 Seveso residents aged 0-19 years—10-year follow-up, mortality All cancers Leukemias Lymphatic leukemia Myeloid leukemia Leukemia, others Central nervous system tumors Australian Vietnam veterans' children— Validation Study AML Wen et al., 2000 Case-control study of children's leukemia (AML and ALL)
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From page 429... ...
In general, it was thought that with paternal exposure that there would be a reduction in the frequency of female offspring since sex-linked lethals on the paternal X chromosome would differentially affect female conceptuses. Investigators have evaluated the sex ratio among various species in relation to exposures such as radiation for a number of years.
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From page 430... ...
(2000) have recently published new findings on the sex ratio of births to parents from Seveso, Italy, where an explosion of a chemical plant resulted in widespread environmental exposure in 1976.
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From page 431... ...
Conclusions Strength of the Evidence in Epidemiologic Studies Newly available information from the Seveso cohort, although interesting, does not change the committee's conclusion that there is inadequate or insufficient evidence to determine whether an association exists between exposure to the herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and altered sex ratio.
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From page 432... ...
There is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides and altered hormone levels, semen quality, or infertility; spontaneous abortion; late-fetal, neonatal, or infant death; low birthweight or preterm delivery; birth defects other than spine bifida; childhood cancers other than AML; and altered sex ratio. Biologic Plausibility This section summarizes the general biologic plausibility of a connection between exposure to dioxin or herbicides and reproductive and developmental effects on the basis of data from animal and cellular studies.
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From page 433... ...
Administration of TCDD to male rats, mice, guinea pigs, marmosets, monkeys, and chickens elicits reproductive toxicity by affecting testicular function, decreasing fertility, and decreasing the rate of sperm production. Effects on the prostate have been seen following TCDD exposure.
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From page 434... ...
Because of the many species and strain differences in TCDD responses, however, controversy remains regarding the TCDD exposure level that causes reproductive or developmental effects. Limited information is available on reproductive and developmental effects of the herbicides discussed in this report.
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From page 435... ...
Investigating the biological mechanisms underlying TCDD's toxic effects continues to be a very active area of research, and subsequent updates of this report might have more and better information on which to base conclusions, at least for that compound. Increased Risk of Disease Among Vietnam Veterans As discussed in Update 1998, there are some data suggesting that the highest risks for spine bifida occur in the children of those veterans estimated to have been exposed to Agent Orange (e.g., Ranch Hands)
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From page 436... ...
1984. Low birthweight.
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From page 437... ...
1984b. Vietnam veterans' risks for fathering babies with birth defects.
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From page 438... ...
The use of offspring sex ratios to detect reproductive effects of male exposure to dioxins. Environmental Health Perspectives 105(2)
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From page 439... ...
1998. Polychlorinated biphenyls in blood plasma among Swedish female fish consumers in relation to low birthweight.
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