7
REPRODUCTIVE AND DEVELOPMENTAL OUTCOMES

This chapter examines reproductive and developmental outcomes of exposure to fuel and combustion products. The outcomes of interest include infertility, preterm birth and low-birth rate, as well as birth defects and childhood cancers.

In previous reports, Institute of Medicine committees focused primarily on exposures that occurred in men and women before conception. Preconception exposure was considered the most relevant to the Gulf War veterans’ experience. Those committees assumed that pregnancies during Gulf War deployment would have been rare that pregnant women would have been immediately evacuated. A newly published study (Araneta et al. 2004), however, indicates that there were many more pregnancies than previously reported and that pregnancies were typically ascertained 2–6 weeks after conception. Thus, it is likely that most pregnant women would have been evacuated during the first 6–12 weeks of pregnancy; that inference led the present committee to expand its search of the epidemiologic literature to include reproductive outcomes, with relevant environmental exposures, during the first trimester of pregnancy.

STUDIES OF BIRTH DEFECTS IN GULF WAR VETERANS

Several studies investigated reproductive effects of service in the Gulf War. Most were of birth defects, and none analyzed whether effects were related to specific biologic or chemical compounds. Early studies did not find any adverse effects, but more recent ones have reported excess cardiac birth defects and other adverse reproductive outcomes in offspring of men and women who served in the Gulf War.

Early studies of Gulf War veterans failed to identify an excess of birth defects in offspring of deployed vs nondeployed veterans. A small study of two Mississippi National Guard units deployed to the Gulf War (n=282) found no excess rate of birth defects in National Guard members’ children compared with rates expected on the basis of surveillance systems and previous surveys (Penman et al. 1996). A much larger study of all live births in military hospitals (n=75,000) in 1991–1993, included a comparison population of births to nondeployed personnel. The risk of birth defects was the same in children of Gulf War personnel as in the control population (Cowan et al. 1997). The study was limited to military hospitals and thereby excluded persons not being cared for in those hospitals (for example, members of the National Guard, reservists, and those who left the military over the course of the study). National Guard



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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 7 REPRODUCTIVE AND DEVELOPMENTAL OUTCOMES This chapter examines reproductive and developmental outcomes of exposure to fuel and combustion products. The outcomes of interest include infertility, preterm birth and low-birth rate, as well as birth defects and childhood cancers. In previous reports, Institute of Medicine committees focused primarily on exposures that occurred in men and women before conception. Preconception exposure was considered the most relevant to the Gulf War veterans’ experience. Those committees assumed that pregnancies during Gulf War deployment would have been rare that pregnant women would have been immediately evacuated. A newly published study (Araneta et al. 2004), however, indicates that there were many more pregnancies than previously reported and that pregnancies were typically ascertained 2–6 weeks after conception. Thus, it is likely that most pregnant women would have been evacuated during the first 6–12 weeks of pregnancy; that inference led the present committee to expand its search of the epidemiologic literature to include reproductive outcomes, with relevant environmental exposures, during the first trimester of pregnancy. STUDIES OF BIRTH DEFECTS IN GULF WAR VETERANS Several studies investigated reproductive effects of service in the Gulf War. Most were of birth defects, and none analyzed whether effects were related to specific biologic or chemical compounds. Early studies did not find any adverse effects, but more recent ones have reported excess cardiac birth defects and other adverse reproductive outcomes in offspring of men and women who served in the Gulf War. Early studies of Gulf War veterans failed to identify an excess of birth defects in offspring of deployed vs nondeployed veterans. A small study of two Mississippi National Guard units deployed to the Gulf War (n=282) found no excess rate of birth defects in National Guard members’ children compared with rates expected on the basis of surveillance systems and previous surveys (Penman et al. 1996). A much larger study of all live births in military hospitals (n=75,000) in 1991–1993, included a comparison population of births to nondeployed personnel. The risk of birth defects was the same in children of Gulf War personnel as in the control population (Cowan et al. 1997). The study was limited to military hospitals and thereby excluded persons not being cared for in those hospitals (for example, members of the National Guard, reservists, and those who left the military over the course of the study). National Guard

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 and reserve troops, as noted earlier, constituted a relatively high percentage of US troops deployed to the Gulf War. Anecdotal reports of an excess of Goldenhar syndrome, a rare congenital anomaly that affects the development of facial structures, prompted another study of birth defects. The syndrome is not specifically coded in the reporting of birth defects, so the authors reviewed medical records of birth-defect categories that would have subsumed the Goldenhar syndrome. Too few cases of the syndrome were found to support definitive conclusions (Araneta et al. 1997). A large, population-based Department of Veterans Affairs study of 15,000 US Gulf War veterans vs 15,000 non-deployed veterans found that both male and female veterans self-reported higher rates of birth defects among liveborn infants, including “moderate to severe” defects (odds ratios [ORs] 1.8–2.8). The defects were grouped into broad categories; the largest (n=151) was described as “isolated anomaly”. Male veterans self-reported a higher rate of miscarriage among their partners (OR 1.62, 95% confidence interval [CI] 1.32–1.99) than did controls. Concerned about reporting bias, the investigators suggested that those observations be confirmed by a review of medical records (Kang et al. 2001). A population-based study in several states captured births in all hospitals, both military and civilian, and matched birth certificates with military records during the period 1989–1993 (Araneta et al. 2003). The study measured the prevalence of birth defects among infants of Gulf War veterans and non-deployed veterans in states that conducted active case ascertainment of birth defects. Military record of 684,645 Gulf War veterans and 1,587,102 non-deployed veterans were electronically linked with 2,314,908 birth certificates from Arizona, Hawaii, Iowa, and selected counties of Arkansas, Califonia, and Georgia; 11,961 Gulf War veterans’ infants and 33,052 non-deployed veterans’ infants were identified. Of those, 450 infants had mothers who served in the Gulf War and 3966 had non-deployed veteran mothers. After examining 48 specific categories of birth defects, the study found a greater prevalence of three defects—tricuspid valve insufficiency (relative risk [RR] 2.7, 95% CI 1.1–6.6), aortic valve stenosis (RR 6.0, 95% CI 1.2–31.0), and renal agenesis (RR 2.4, 95% CI 0.7–8.3)—in infants conceived after the war by Gulf War-deployed men in comparison with non-Gulf War-deployed men. Aortic valve stenosis and renal agenesis had higher RRs among infants conceived after the war by Gulf War veteran men than among infants conceived before the war. The study also found a greater prevalence of hypospadias in male infants (RR 6.3, 95% CI 1.5–26.3) conceived during or after the war and born to female Gulf War veterans (in comparison with non-Gulf War-deployed females). The study was not designed to determine whether the excess risk was caused by environmental agents, and it should be interpreted as an exploratory study that investigated 48 categories of birth defects. A recently published population-based UK study probed the prevalence of birth defects and fetal deaths in all UK Gulf War veterans and Gulf War-era controls (that is, veterans who were not deployed to the gulf war)—a total of 105,735 veterans—studied with a validated postal questionnaire (Doyle et al. 2004). The study period covered conception after the Gulf War and before November 1997. Male Gulf War veterans reported a higher risk of miscarriages in their partners than the comparison cohort (OR 1.4, 95% CI 1.3–1.5). They also reported a higher proportion of offspring with any type of malformation (OR 1.5, 95% CI 1.3–1.7). Examination by type of malformation revealed some evidence of an increased risk of malformation but it was weakened when the analyses were restricted to clinically confirmed conditions. Female veterans did not report an excess of miscarriage, and stillbirths and malformations were too few to be usefully analyzed.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Five reproductive outcomes (livebirth, stillbirth, spontaneous abortion, ectopic pregnancy, and induced abortion) were analyzed among female veterans during or after the Gulf War compared to nondeployed female veterans (Araneta et al. 2004). A postal survey was sent to every woman identified by the Department of Defense as having a pregnancy-related admission to a military hospital from August 2, 1990 to May 31, 1992. The responses were validated with medical records; it was observed that female veterans with post-Gulf War conceptions (n=292) were at increased risk for spontaneous abortion (OR 2.92, 95% CI 1.9–4.6) and ectopic pregnancy (OR 7.70, 95% CI 3.0–19.8) compared with nondeployed female veterans (n=427). No difference was found between pregnancies of Gulf War-deployed women and those of non-Gulf War-deployed women. FUELS AND REPRODUCTIVE AND DEVELOPMENTAL OUTCOMES In reviewing the literature on paternal and maternal exposure to fuels, the committee found several studies on adverse reproductive outcomes, including infertility, spontaneous abortion, childhood leukemia, neuroblastoma, and Prader-Willi syndrome—which may result from genetic alterations in either sperm or egg. The studies related to each of those outcomes are discussed below (Table 7.1). TABLE 7.1 Selected Epidemiologic Studies—Reproductive Outcomes and Exposure to Fuel Reference Population Exposed Cases Estimated Relative Risk Acute nonlymphocytic leukemia Case-Control Study Buckley et al. 1989 Paternal exposure to petroleum products       None 93 1.0 1–1,000 days duration 32 1.4 (0.8–2.5) > 1,000 days duration 53 2.4 (1.3–4.1) Before conception NA 2.0 (p<0.05) During gestation NA 2.8 (p<0.05) Leukemia Case-Control study Shu et al. 1988 Maternal occupational exposure during pregnancy       Gasoline 38 1.6 (0.8–3.1) Diesel oil 16 1.4 (0.6–3.3) Kerosene 16 1.4 (0.6–3.1) Maternal occupational exposure during pregnancy by histopathologic cell type     Gasoline     ANLL 13 2.1 (1.1–4.3) ALL 21 1.7 (1.0–3.0) Kerosene     ANLL 6 2.3 (0.9–6.3) ALL 9 1.5 (0.6–3.4)

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Reference Population Exposed Cases Estimated Relative Risk Neuroblastoma Case-Control Studies De Roos et al. 2001 Maternal occupational exposure     Nonvolatile hydrocarbons, self-reported exposure 26 1.2 (0.7–2.2)   Nonvolatile hydrocarbons, industrial hygienist reviewed exposure 12 1.1 (0.5–2.5) Diesel fuel, self-reported exposure 12 1.3 (0.5–3.1) Diesel fuel, industrial hygienist reviewed exposure 3 0.9 (0.2–4.4) Gasoline, self-reported exposure 14 1.6 (0.6–3.8) Gasoline, industrial hygienist reviewed exposure 3 0.8 (0.2–4.2) Paternal occupational exposure     Nonvolatile hydrocarbons, self-reported exposure 130 1.3 (0.9–1.9) Nonvolatile hydrocarbons, industrial hygienist reviewed exposure 91 1.5 (1.0–2.2) Diesel fuel, self-reported exposure 72 1.2 (0.8–1.9) Diesel fuel, industrial hygienist reviewed exposure 42 1.5 (0.8–2.6) Kerosene, self-reported exposure 26 1.1 (0.6–2.0) Kerosene, industrial hygienist reviewed exposure 16 1.0 (0.5–2.2) Gasoline, self-reported exposure 77 0.8 (0.5–1.2) Gasoline, industrial hygienist reviewed exposure 45 0.8 (0.5–1.3) Adjusted for frequently co-occurring hydrocarbons and paints for paternal exposure to diesel fuel NA 2.0 (1.0–4.3) Kerr et al. 2000 Maternal exposure to petroleum 23 3.0 (1.5–6.1)   Paternal exposure to petroleum 53 1.8 (1.1–2.8) Prader-Willi syndrome Case-Control Study Cassidy et al. 1989 Paternal occupational exposure to hydrocarbons 24 0.72 (0.28–1.81) Infertility Infertility is the inability to conceive after at least 12 months of unprotected intercourse (Rowe et al. 1993). It has been estimated that 10–15% of couples of reproductive age experience some form of infertility (Speroff et al. 1999). There are numerous risk factors for infertility including: advanced age, obesity in women, previous reproductive experiences, genetic factors, and such diseases as chlamydial infection in women and epididymitis in men (Templeton 2000). No studies of infertility in women and exposure to fuels met the committee’s inclusion criteria (see Chapter 2) but the committee found one study on semen characteristics. In men, semen samples can be collected and used to assess sperm production, structure, and function as measures of the effect of exposure on the male reproductive system. A prospective study was conducted to evaluate the effects of mixed, low-level exposure to complex mixtures on reproductive potential in men (Lemasters et al. 1999). The study included 50 men

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 working on aircraft maintenance at an Air Force installation and eight nonexposed men at the same facility. Semen quality was assessed at baseline, before entry into the exposed job, and at periods of 15 and 30 weeks post-baseline, during which the men were occupationally exposed to solvents or jet fuels (primarily JP4). Although those two periods were chosen to allow for two complete cycles of spermatogenesis, the distal regions of the epididymis contain sperm of different ages. At baseline (before entry into the workplace) semen was collected but there was no exposure monitoring. For 15 and 30 weeks of occupational exposure, semen assays and exposure assessment—with industrial-hygiene monitoring and breath sampling—were conducted for the exposed group, and only semen assays were requested for the nonexposed office workers. Overall, for most sperm measures, the mean values remained within normal range throughout the 30 weeks of exposure. The findings by cycle for all exposed subjects were compared with reference values, and all semen measures at all cycles were found to be similar to reference limits except for percent motile,1 which was consistently lower. The eight nonexposed subjects had sperm measures similar to the exposed group, and their percent motile was also lower at baseline than the reference. Thus, the findings indicate that exposure to jet fuel did not have an apparent effect on semen quality of aircraft-maintenance personnel. Two possible explanations for the findings are that the mixtures are not associated with spermatotoxic effects at low concentrations and that the exposure measured at one point may be inadequate for characterizing the true absorbed dose. The strengths of the study were that analyses were adjusted for potential confounders, including alcohol, smoking, and caffeine. Limitations of the study include the appreciable differences in age among the men in the different job groups and the low statistical power. Spontaneous Abortion The most common cause of spontaneous abortion is a genetic abnormality of the embryo. Risk factors for spontaneous abortion include age, maternal illness, cigarette-smoking, alcohol use, use of some medications, and a previous spontaneous abortion. The risk of pregnancy loss is known to increase with maternal age, especially after the age of 30 or 35 years; and is also high in women under the age of 18 years. In a woman who has had one spontaneous abortion, the probability of a second is estimated to be 13–26%; and the probability of another increases with successive spontaneous abortions (Smith and Suess 1998). Several maternal occupational exposures have been associated with the risk of spontaneous abortion, including exposure to ethylene oxide, antineoplastic agents, and possibly anesthetic gases. Spontaneous abortion was studied in women living near oil fields in the Amazon basin of Ecuador (San Sebastián et al. 2002). The water in the rivers and streams of that area is contaminated with oils and is used for drinking, cooking, and bathing. Women living in several communities downstream of oil fields (n=365) were compared with women living upstream and farther from the fields (n=283). The concentration of total petroleum hydrocarbons in drinking water were 0.02 to 2.88 ppm in exposed communities. After adjustment for confounders, women in exposed communities were more likely to report pregnancies ending in spontaneous abortion (OR 2.47, 95% CI 1.61–3.79, p<0.01). The multivariate analysis adjusted for age at interview, age at pregnancy, pregnancy order, year of pregnancy, and socioeconomic status (SES). 1   Percent motile depends on time from ejaculation until sample analysis.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Limitations of the study include the assignment of the same exposure status, based on drinking-water measurements, to every woman in a given study area, and the potential for recall bias. Childhood Cancers The committee considered any health effect in the child of a veteran as a reproductive effect even if the manifestation was cancer. Childhood cancer is defined by the American Cancer Society as cancer diagnosed between birth and the age of 14 years. The causes of most childhood cancers are not well known, especially with regard to potential environmental risk factors. Some of the suggested risk factors are genetics, advanced maternal age, birthweight of more than 4000 g, prenatal viral exposure, and prenatal radiation exposure (Ross and Swensen 2000). Developments in treatment and supportive care for some types of cancer have enabled 75% of afflicted children to survive 5 years or more, and mortality from all childhood cancers combined has declined by 50% since 1973. Although childhood cancer is rare, it is still the leading cause of death from disease in children up to 14 years old (ACS 1999). Leukemia Leukemia is the most common cancer in children and accounts for almost one-third of all cases of childhood cancer. Acute lymphocytic leukemia (ALL) is the most common leukemia in children, accounting for nearly 75% of all leukemia cases (ACS 2002b). Slightly more prevalent among white children and among boys, ALL generally occurs in early childhood, particularly at the age of 2–3 years. The 5-year survival rate of children who have ALL has increased to nearly 80%, primarily because of advances in treatment (ACS 2002b). Most of the remaining childhood leukemia cases are categorized as acute myeloid leukemia (AML), which occurs most commonly in the first 2 years of life and less commonly among older children. Developments in treatment have improved the survival rate of children who have AML, who have 5-year survival rate of about 40% (ACS 2002b). Prenatal exposure to radiation is known to be associated with the development of ALL (IARC 2000). Some genetic disorders—such as Li-Fraumeni syndrome, Down syndrome, and Klinefelter syndrome—also are associated with ALL, and chemotherapeutic agents are associated with secondary leukemia later in childhood or in adulthood. A population-based case-control study of 204 children under the age of 18 years who had acute nonlymphocytic leukemia (ANLL) or AML examined occupational exposures of parents (Buckley et al. 1989). The cases were age-matched to population controls, and all the mothers were interviewed, as were the fathers if available. During the interviews, information was collected on demographics, occupational histories and exposures, household exposures, lifestyle factors, reproductive and medical histories, complications of delivery, and congenital abnormalities of the child and first-degree relatives. For each exposure, the nature of the exposure, duration, frequency, and timing in relation to the index pregnancy was asked of each parent. All exposures and related information were self-reported. During the interviews, the parents were asked to report occupational exposures to 52 agents, including petroleum products. Among fathers who had been exposed to petroleum products for more than 1,000 days, the OR for ANLL was 2.4 (95% CI 1.3–4.1; p trend=0.002) for exposure at any time before, during, or after the birth. The point estimate of the risk decreased to 2.0 for paternal exposure only before conception.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 A population-based case-control study of 309 children who had leukemia and 618 healthy population controls in urban Shanghai, China, was conducted (Shu et al. 1988). Controls were randomly selected from the Shanghai general population and matched on sex and age. Information on parental lifestyle, radiation exposure, medication use, birth characteristics, and parental occupation was collected through in-person interviews. Maternal and paternal occupations during pregnancy included working in the chemical industry or a related occupation, working in agriculture or metal refining and processing, being a physician or pharmacist, and working in pharmacy manufacturing. Paternal occupation during pregnancy had no influence on the occurrence of leukemia. There were increased adjusted ORs for maternal exposure to gasoline (OR 1.6, 95% CI 0.8–3.1), diesel oil (OR 1.4, 95% CI 0.6–3.3), and kerosene (OR 1.4, 95% CI 0.6–3.1). Risk by leukemia type showed an association between maternal gasoline exposure and ANLL (OR 2.1, 95% CI 1.1–4.3) and ALL (OR 1.7, 95% CI 1.0–3.0) and between exposure to kerosene and ANLL (OR 2.3, 95% CI 0.9–6.3) and ALL (OR 1.5, 95% CI 0.6–3.4). According to the authors, limitations of the study include recall bias (cases were diagnosed over a 12-year period, whereas controls were healthy children selected in 1985–1986) and interviewer bias (trained interviewers could not be blinded to case-control status). Furthermore, the control-selection procedures might have resulted in bias in the favoring of children from large residential areas. Finally, multiple comparisons in the study and lack of validation for parental x-ray, drug, or occupational exposure indicate the need for cautious interpretation. Four additional studies examined the relationship between parental occupation and childhood leukemia (Gold et al. 1982; Hakulinen et al. 1976; Lowengart et al. 1987; van Steensel-Moll et al. 1985). They were limited by their inability to validate employment history and their lack of details on specific assessment of exposure as in the study by Shu et al. above (1988). The broad exposure group “hydrocarbon related” included many diverse occupations with exposures to chemicals in addition to hydrocarbons, therefore, it is difficult to draw conclusions on exposure to fuels. Three of those studies did not find increased risks of leukemia related to hydrocarbon- or petroleum-product-exposed parental occupations, either before or during pregnancy. The study of van Steensel-Moll (1985) found that maternal exposure to paint, petroleum products, and unspecified chemicals during pregnancy was related to childhood leukemia (RR 2.4, 95% CI 1.2–4.6). No particular periods of pregnancy were specified. Central Nervous System Cancer Central nervous system (CNS) cancers include malignant brain and spinal-cord tumors. Brain tumors are the second-most common group of cancers in children, accounting for about 20% of all childhood cancers. Common types of childhood brain tumors are astrocytomas (tumors originating in the brain cells), primitive neuroectodermal tumors (PNETs, tumors that develop from primitive stem cells), and germ-cell tumors. Neuroblastoma, a type of CNS tumor derived from embryonic neural crest cells, is a common form of cancer in children and accounts for 7–10% of all childhood cancers (ACS 2002a). The etiology of childhood brain cancer appears to be multifactorial; there is no clear primary cause. Such genetic syndromes as Li-Fraumeni syndrome and von Recklinghausen disease are known to be associated with a modest fraction of these tumors. One well-established risk factor for the development of brain tumors is exposure to ionizing radiation, which can occur during the treatment of other cancers. Other factors—such as exposure to nitrates, aspartame, and electromagnetic fields—have been studied, but no conclusive evidence clearly implicates them

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 as causal factors. More than 50% of children with brain tumors (all types combined) survive over 5 years (ACS 2002a). To study the effects of parental occupational exposure on the incidence of neuroblastoma among children, De Roos et al. (2001) conducted a case-control study of 538 incident cases of neuroblastoma in children under the age of 19 years who had a new and confirmed diagnosis of neuroblastoma and registered at 139 participating hospitals in the US and Canada. Cases were age-matched to controls 1:1 recruited with random-digit dialing. Telephone interviews were conducted with all the mothers, and fathers if available, to obtain information on demographic characteristics, occupational histories, and exposures to specific chemicals. For each job held during the 2-year period before a child’s date of birth, the mother and father were asked specifically about 65 chemicals, including the category of “nonvolatile hydrocarbons” and such specific agents as petroleum products, oils and lubricants, cutting oil, diesel fuel, kerosene, and lubricating oil or grease. All self-reported exposures were reviewed by an industrial hygienist in an attempt to reduce the number of incorrect reports of exposures. Maternal exposure to most chemicals was not associated with neuroblastoma; however, paternal exposure to some hydrocarbons was associated with increased incidence of neuroblastoma. The OR for neuroblastoma related to self-reported paternal exposure to diesel fuels was 1.2 (CI 0.8–1.9), to kerosene 1.1 (CI 0.6–2.0), and to gasoline 0.8 (CI 0.5–1.2). The analyses were rerun using an industrial hygiene review to assign exposure; the OR for diesel fuel was 1.5 (CI 0.8–2.6), for kerosene 1.0 (CI 0.5–2.2), and for gasoline 0.8 (CI 0.5–1.3); adjustment did not indicate increased risk. The authors noted that they were unable to explore effects of maternal and paternal exposure before conception or during pregnancy separately because exposures overlapped during those periods. The large number of chemicals considered and the retrospective assessment of exposure limit the strength of this study. Overall, the study found weak support for an association between paternal exposure to diesel fuel and neuroblastoma and no support for an association between maternal exposures to any of the chemicals and neuroblastoma. In another case-control study, interviews were conducted with the mothers and fathers of 183 children 0–14 years old who had neuroblastoma and resided in New York state (excluding New York City) and with the parents of 372 controls selected from the New York state live-birth certificate registry and matched to cases on year of birth (Kerr et al. 2000). Occupational histories and exposure information on 25 specific physical and chemical compounds were collected for both parents. Information was collected on parental occupation during the entire pregnancy with the index child. Mothers reported both their own and the fathers’ occupational histories. An increased risk of neuroblastoma was associated with maternal and paternal exposure to petroleum (OR 3.0, 95% CI 1.5–6.1 and OR 1.8, 95% CI 1.1–2.8, respectively). According to the authors, limitations of the study include possible misclassification of job and exposure, the increased likelihood of chance findings due to the large numbers of multiple comparisons, potential interviewer bias because interviewers were not blinded to the disease status of the index child of the mother being interviewed, and collection of exposure information on both parents from mothers. A case-control study of occupational exposures of parents with children who had astrocytoma (n=155) or PNET (n=166) was conducted (Bunin et al. 1994). Cases were compared with matched control children who were identified with random-digit dialing. Kerosene was the only exposure of relevance to this committee, but the study explored an array of occupational and lifestyle exposures. The study found that maternal exposure to kerosene

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 during pregnancy was associated with an increased risk of astrocytoma (OR 8.9, 95% CI 1.1–71.1, p=0.04). No specific information on the nature of the exposure was provided, and the study carries the potential for recall bias. Prader-Willi Syndrome Prader-Willi syndrome (PWS) is a neurogenetic disorder generally associated with an abnormality of chromosome 15. About 60–75% (Akefeldt et al. 1995) of patients with PWS have a cytogenetically visible deletion in the q11–q13 region of paternal chromosome 15. Because PWS is highly associated with the loss of paternally derived genetic material, some have speculated that environmental factors may lead to PWS in men’s offspring (Magenis 1988; Strakowski and Butler 1987). The incidence of PWS is 1 in 12,000 affecting both sexes and various races equally. Children with PWS are often characterized as short and having mental retardation or learning disabilities, incomplete sexual development, behavior problems, low muscle tone, and an urge to eat constantly, which often leads to obesity (PWSA 2004). Akefeldt et al (1995) conducted a case-control study of 15 PWS patients and 13 controls to assess the relationship between PWS and parental exposures to hydrocarbons, including gasoline. The PWS patients were referred by pediatric outpatient departments. The controls were children referred for obesity that had mental retardation but did not fulfill all the diagnostic criteria for PWS. The study did not include a “normal” control group. Both parents of each child completed a questionnaire about their exposure to environmental and occupational agents (for example, gasoline, petrochemicals, and pesticides). Seven of the 15 PWS fathers reported exposure to gasoline (p=0.01) compared with none in the control group. The fathers reported that they had been exposed for 5–17 years (mean, 9 years) before the children’s conceptions. Among the seven PWS children whose fathers had been exposed to gasoline, five had molecular genetic deletions. Four of the eight PWS children, whose fathers were not exposed to gasoline also had chromosomal deletions. One PWS mother and two control group mothers reported exposure to gasoline. The results of the study indicate that only gasoline, not hydrocarbons in general, is implicated in the etiology of PWS. However, the authors note that the small number of cases makes it difficult to obtain significant values. Given the difficulty in correctly recalling details about exposure, especially the duration of exposure, the possibility of errors cannot be excluded. An earlier study found an association between PWS and paternal occupational hydrocarbon exposure at or about time of conception (Strakowski and Butler 1987). The study included 652 PWS patients identified from the National Prader-Willi Syndrome Association. To obtain controls with a genetic disease in which paternal environmental exposure was an unlikely causative factor, the authors chose fragile X syndrome (n=66) and Down syndrome (n=268). The average age of the fathers was 32 years, no different from the national average. Occupations were classified into 23 categories; 12 categories involved considerable occupational exposure to hydrocarbons, and five to lead. The percentage of fathers with unknown occupations was similar in the PWS group (7.1%) and in the controls (7.5%), and they were excluded from statistical calculations. Paternal occupational hydrocarbon exposure in the PWS group (20.8%) was greater than that in the controls (12.0%), (p-value <0.001). Although the Akefeldt et al. and Strakowski and Butler studies found associations between PWS and paternal hydrocarbon or gasoline exposure, neither study collected information on potential confounders, such as paternal drug use, radiation exposure, or smoking

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 history. However, despite the lack of control for potential confounders, the consistent associations found in both studies, the presence of paternal chromosomal deletions in 60–75% of PWS patients, and studies showing associations between chromosomal aberrations and occupational exposure to gasoline (Carere et al. 1998; Khalil 1995; Santos-Mello and Cavalcante 1992) suggest that it is biologically reasonable that paternal exposure to hydrocarbons, such as gasoline, is a possible mechanism for paternally derived PWS. Studies have also shown that in nearly all cases involving an interstitial chromosomal deletion in PWS patients (Ledbetter and Cassidy 1988), parental chromosomes have been normal; thus the deletion in PWS patients might be a de novo event. To explore the hypothesis that hydrocarbon exposure was associated with the chromosomal abnormality in PWS, Cassidy et al. (1989) conducted a study to determine whether there was a difference in the prevalence of occupational exposure to hydrocarbons at the time of conception between fathers of PWS children who have a 15q chromosomal deletion and fathers of PWS children who do not have such a deletion. Using job classification, they assigned exposure to hydrocarbons. Of the 53 fathers of children with 15q deletions, 24 (45%) were engaged in potentially hydrocarbon-exposed occupations compared with 15 (54%) of the 28 fathers of children with apparently normal chromosomes (OR 0.72, 95% CI 0.28–1.81). Although there were no differences in exposure history on the basis of the presence of 15q deletions, the authors recognize that they were unable to determine whether submicroscopic deletions may be present in the children without apparent chromosome abnormalities. They suggest that research on smaller, less visible microdeletions is needed to understand the relationship between hydrocarbon exposure and PWS. Conclusion Overall, it is difficult to reach conclusions on the epidemiologic studies of adverse reproductive outcomes and exposure to fuels. Assessment of findings is limited by the small number of studies available on each health outcome, the possibility of recall bias, and the lack of specificity of exposure to the agents of concern in this report. The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to fuels and adverse reproductive or developmental outcomes, including infertility, spontaneous abortion, childhood leukemia, central nervous system tumors, neuroblastoma, and Prader-Willi syndrome. COMBUSTION PRODUCTS AND REPRODUCTIVE AND DEVELOPMENTAL OUTCOMES This section covers the following outcomes that have been addressed in epidemiologic research in relation to combustion-product exposures: preterm birth, low birthweight (LBW), very low birthweight (VLBW), intrauterine growth retardation (IUGR), birth defects, and childhood cancers.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Adverse Pregnancy Outcomes The committee sought information on whether maternal or paternal exposure to combustion products before conception or maternal exposure during the first 3 months (first trimester) of gestation affected pregnancy outcomes. A number of adverse outcomes of pregnancy have been studied for possible associations with exposure to combustion products in air pollution. Most studies examined adverse effects on live births including preterm birth, IUGR, and LBW, which have a pronounced influence on infant morbidity and mortality (Pschirrer and Monga 2000). In the studies covered in this chapter, IUGR and LBW were usually analyzed in relation to full-term births. Other studies examined stillbirths or birth defects. The studies reviewed in this section, conducted largely in heavily polluted cities worldwide, examined associations between adverse pregnancy outcomes and combustion products. Preterm Births Preterm birth (<37 weeks) is the second leading cause of infant mortality in the United States (MMWR 1999) and a major cause of infant morbidity. Known environmental risk factors include maternal cigarette-smoking and alcohol dependence; other risk factors are a history of preterm birth, maternal race, and multiple gestation (Pschirrer and Monga 2000). Most preterm births in the United States do not result in LBW (Ritz et al. 2000). At least seven studies, in different continents, have explored the effects of air pollution on preterm births (Table 7.2). The effects of air pollution on preterm births were studied in a cohort of nearly 100,000 births in Los Angeles in 1989–1993 (Ritz et al. 2000). The exposure, based on collections at 17 air quality monitoring stations, was of averaged pollutant measures over distinct periods such as 1, 2, 4, 6, 8, 12, and 26 weeks before birth, and the entire pregnancy period. The authors also calculated average exposures in the first and second month of pregnancy. Pollutants of interest were carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3), and PM10 (particulate matter 10 μg in diameter). About 9% of infants in the sample were born preterm. For PM10, a 50-μg/m3 increase in concentration over the first month of pregnancy was associated with a 16% increase in the rate of preterm births (RR 1.16, 95% CI 1.06–1.26). For CO, a 3-ppm increase over the first month of pregnancy was associated with a 4% increase in the rate of preterm births (RR 1.04, 95% CI 1.01–1.09). This study was well designed, with analyses controlling for several known risk factors for preterm birth, including age, race, education, parity, access to prenatal care, and previous low-birthweight or preterm births. The authors adjusted for maternal smoking but reported that the adjustment was incomplete.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Reference Population Pollutant Measured and Exposure Period Adjusted OR (95% CI or p) by Period and Pollutant Adjustments Limitations Wang et al. 1997 74,671 live births, China 1988–1991 SO2, TSP LBW: Gestational age, residence, year of birth, maternal age, and infant sex. No adjustment for maternal smoking, but few women in China during study period smoked, so smoking unlikely to be important confounder Trimesters 1–3 SO2 per 100-μg/m3 increase Trimesters 1, 2 NS after adjusting for trimester 3 Trimester 3: OR 1.11 95% CI 1.06–1.16 TSP per 100-μg/m3 increase Trimesters 1, 2 NS after adjusting for Trimester 3 Trimester 3: OR 1.10 95% CI 1.05–1.14 Ritz & Yu 1999 125,573 live births, Los Angeles 1989–1993 CO LBW: Gestational age; female child; maternal race, education, age; no prenatal care; and so on Did not examine trimesters 1–2 Trimester 3 CO: 2.2 to <5 ppm OR 1.04, 95% CI 0.96–1.13 ≥5 ppm OR 1.22, 95% CI 1.03–1.44

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Two studies of full-term births were published in the Czech Republic (Dejmek et al. 1999, 2000). One of the primary sources of particles in those populations is coal combustion. The first study was of all live singleton births in the heavily polluted district of Teplice, Czech Republic, covering the period 1994–1996 (Dejmek et al. 1999), and the second study covered the years 1994–1998 (Dejmek et al. 2000). The first study examined the effects of PM10 exposure during each month of pregnancy. Of the 1,943 enrolled women who gave birth to full-term singleton infants (at 37–43 weeks of gestation), nearly 10% delivered a child who had IUGR. The study also collected information from questionnaires and medical records in addition to vital statistics and environmental monitoring. After adjustment for relevant confounders—including maternal smoking, year, and season—there were associations between IUGR and PM10 and PM2.5 exposure during the first month of pregnancy. In particular, the OR for medium exposure to PM10 was 1.62 (95% CI 1.07–2.50) and for high exposure 2.64 (95% CI 1.48–4.71); for PM2.5, the OR for medium exposure was 1.26 (95% CI 0.81–1.95) and for high exposure 2.11 (95% CI 1.20–3.70). ORs for exposures during the other 8 months of pregnancy were mostly close to 1.0. The study was well designed and statistically powerful, controlling for relevant risk factors and assessing first-trimester exposure separately from exposure in other periods. Another study (Dejmek et al. 2000) examined whether exposure to polycyclic aromatic hydrocarbons (PAHs), usually bound to fine particles, was associated with IUGR in full-term births. The study included a comparison district (Prachatice) with lower pollution. This study was not an independent dataset from the earlier Dejmek et al. study discussed above. It expanded the period of study to 4 years and was designed to explore associations with components of the particles. In multivariate models that adjusted for confounders, higher PAH concentrations during the first month of gestation increased the risk of IUGR and the adjusted ORs were 1.59 (95% CI 1.06–2.39) for medium exposure and 2.15 (95% CI 1.27–3.63) for high exposure. The authors concluded that the risk of delivering a growth-retarded infant increased with the concentration of fine particles and PAHs in the first month of gestation. Bobak (2000) conducted a study of all singleton live births registered in 1991 by the Czech Republic (n=126,752 singleton live births). The study linked Czech national birth-register data with area-based measures of air pollution in 67 districts where at least one pollutant was measured (n=108,173). Maternal exposures to outdoor SO2, TSP, and NO2 in each trimester of pregnancy were studied in relation to LBW, IUGR (<10th percentile of birthweight for gestational age and sex) and prematurity (results were given in the previous section). After adjustment for sex of infant, education, parity, age, marital status of mother, and month of birth, LBW was associated with SO2 and TSP (OR 1.2, 95% CI 1.11–1.30 and 1.15, 95% CI 1.07–1.24, respectively, for a 50-μg/m3 increase in mean SO2 and TSP concentrations in first trimester). When gestational age was also adjusted for, the relationship with SO2 was substantially weaker, but the TSP relationship remained strong although the confidence interval widened and included the null value. Prematurity was also associated with SO2, TSP, and NO2 concentrations during the first trimester (as described in the previous section). Associations in the second and third trimesters were similar to those found in the first trimester; this was expected because there were correlations between pollutants across trimesters. One potential limitation of the study is the lack of control for maternal smoking, a risk factor for LBW. A study explored the relationship between LBW and exposure to air pollution in South Korea during different gestational phases (Lee et al. 2003). Birthweight was extracted from birth certificates for all full-term singletons born at 37–44 weeks gestational weeks (n=388,105). Air pollution monitoring data were used to assign exposure during each trimester and each month of

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 pregnancy. After adjustment for sex, birth order, maternal age, parental education level, and gestational age, first-trimester CO and PM10 exposure increased LBW risk (OR 1.04, 95% CI 1.01–1.07 and OR 1.03, 95% CI 1.00–1.07, respectively), as did second-trimester exposure to PM10, SO2, and NO2, for which ORs were generally between 1.03 and 1.06 with narrow confidence intervals reflecting the large sample size. There were positive (small) dose-response relationships between LBW and CO during the first trimester and LBW and PM10 and SO2 during the second trimester. Point estimates of effect in the third trimester ranged between 0.96 and 1.00. In the monthly analyses, the risk of LBW were higher for CO exposure in months 2–5 and for PM10 in months 2–4 than in later months. For SO2 and NO2, exposure in months 3–5 was associated with LBW. Further analyses, dividing exposure into the first 5 months and the last months also suggested that earlier exposure was associated with LBW. Exposure during the first 5 months was associated with LBW even if air pollution was low during the last 5 months. A potential limitation is the lack of control for maternal smoking, a risk factor for LBW. Overall, the study found evidence of an association between LBW and early-pregnancy exposure, primarily during the first 5 months. Liu et al. (2003), as noted in the previous section, explored the relationship between ambient air pollution and preterm birth, LBW, and IUGR among singleton live births in Vancouver, Canada. IUGR was studied only in full-term births. The authors found an increased adjusted OR for LBW and maternal exposure to SO2 during the first month of pregnancy (OR 1.11, 95% CI 1.01–1.22 per 5-ppb increase). The LBW-SO2 association persisted even after adjustment for the other pollutants. IUGR was also associated with exposure to NO2, SO2, CO during the first month of pregnancy but not during the last month. IUGR was associated with SO2 and CO exposure during the first trimester. Overall, the study was of high quality. One potential limitation is the lack of control for maternal smoking, a risk factor for adverse pregnancy outcomes. A study examined the relationship between ambient air pollution in six northeastern US cities and full-term LBW among 89,557 singleton live births (Maisonet et al. 2001). Average exposure during each trimester was estimated for each study subject on the basis of maternal residence from the birth certificate. In the multivariate analyses, an association was found between LBW and third-trimester CO (adjusted OR 1.31 per 1-ppm increase, 95% CI 1.06–1.62). The models adjusted for maternal smoking during pregnancy, alcohol consumption, maternal education, maternal age, maternal race or ethnicity, marital status, weight gain during pregnancy, previous terminations, infant sex, season of birth, prenatal care, gestational age, and other pollutants. No associations were found between LBW and first- or second-trimester CO exposure or between LBW and exposure to PM10 in any trimester. Second-trimester SO2 exposure was not associated with LBW when it was used as a continuous variable; there were some associations when second-trimester SO2 exposure was entered into the models in quintiles. This high-quality study was well designed and statistically powerful. It controlled for relevant risk factors and assessed first-trimester exposure separately from other periods, but found consistent associations only with third-trimester CO exposure. The ORs between LBW and first-trimester exposure to the three pollutants were consistently less than 1.0. A community-based study of all pregnant women in four residential areas of Beijing, China, was conducted (Wang et al. 1997). First-parity single live full-term births (n=74,671) were studied in relation to average TSP and SO2 exposure at various times throughout pregnancy, means during each trimester, and lagged moving averages in weeks before birth. After adjustment, third-trimester exposure to TSP and SO2 was most strongly associated with

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 LBW: ORs increased by a factor of 1.11 for each 100-μg/m3 increase in SO2 (95% CI 1.06–1.16) and 1.10 (95% CI 1.05–1.14) for TSP. The other exposure variables, TSP and SO2 at other times, had little predictive value after adjustment for third-trimester exposure. Most analyses adjusted for gestational age, residence, year of birth, maternal age, and infant sex. Small negative associations between LBW and first- and second-trimester exposure suggested lower risk with higher exposure. Although maternal smoking was not adjusted for, the authors note that few women in China during the study period smoked. Residential exposure to combustion products from burning fuel or cooking are other potentially important confounders which were not adjusted for in this study. Another study examined the effect of ambient CO on LBW among full-term infants in southern California (Ritz and Yu 1999). It limited exposure assessments to the third trimester because there was evidence that smoking-related effects are mediated by hypoxia during the last trimester. Although not directly informative on first-trimester exposures, the study supports associations between LBW and third trimester exposure. For CO exposure at more than 5.5 ppm, there was a 22% increase in LBW (OR 1.22, 95% CI 1.03–1.44). Some published studies (for example, Bobak and Leon 1999; Sram et al. 1996; Vassilev et al. 2001a, 2001b) were cross-sectional or ecologic studies and did not differentiate between early-pregnancy exposure (first trimester) and exposure throughout pregnancy. One study (Perera et al. 2003) was only of third-trimester PAH exposure, and another (Wilhelm and Ritz 2003), although well designed, studied traffic patterns in relation to LBW but did not distinguish between first-trimester exposure and exposure throughout pregnancy. It is not now possible to identify critical periods of gestation during which exposure is associated with increased risks of LBW and IUGR. The data among studies are not consistent: some studies found associations between LBW and early-pregnancy exposure to specific pollutants (for example, Dejmek et al. 1999), between LBW and late-pregnancy exposures to specific pollutants (for example, Maisonet et al. 2001; Ritz and Yu 1999; Wang et al. 1997), or between LBW and exposure to specific pollutants during both early and late pregnancy (for example, Dejmek et al. 2000); others failed to find associations between LBW or IUGR and either early or late exposure to specific pollutants (for example, Bobak 2000; Maisonet et al. 2001). Identifying a specific period of vulnerability is especially difficult because ambient exposures at different times are correlated, and most studies did not adjust for exposure at different points in pregnancy. One study (Lee et al. 2003) attempted to do that and found the most consistent associations with exposures during the first 5 months (that is, the first and second trimesters), a period that overlaps with but is longer than the period of Gulf War exposure. In conclusion, there is inadequate evidence to conclude that early-pregnancy exposure alone, independently of middle- and late-pregnancy exposure to air pollutants, is associated with full-term LBW and IUGR. Although the evidence on exposure during any time during pregnancy and adverse pregnancy end points is accumulating, further studies are needed to determine the relevant exposure time. Studies adjusting for exposure at different times during gestation would be especially informative. The two studies conducted in the Czech Republic (Dejmek et al. 1999, 2000) were well designed studies and found evidence of a relationship between LBW or IUGR and combustion-product exposure. Their analyses controlled for several known risk factors, including maternal smoking. Several other studies reviewed by the committee provide supportive evidence of a relationship (Bobak 2000; Lee et al. 2003; Liu et al. 2003; Maisonet et al. 2001; Ritz and Yu 1999; Wang et al. 1997) but most were unable to adjust for maternal smoking.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 The committee concludes, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of an association between combustion product exposure during pregnancy and low birthweight or intrauterine growth retardation, but the data provided inadequate/insufficient evidence of an association between combustion-product exposure at specific periods during pregnancy (for example, the first trimester) and low birthweight and intrauterine growth retardation. Birth Defects The association between maternal exposure to air pollutants and the risk of birth defects in southern California was studied during 1987–1993 (Ritz et al. 2002). With a population-based, case-control method, average monthly exposure was assigned to birth-defect cases and control pregnancies (n=10,649) on the basis of ambient-air monitoring data related to maternal residence during gestation. Dose-response relationships were found between cardiac defects and increasing exposure to CO and O3 during the second month of gestation. In the case of CO, the risk of ventricular septal defect was increased (ORs per quartile of exposure 1.62–2.95). In the case of O3, the risk of aortic artery and valve defects, pulmonary artery and valve anomalies, and conotruncal defects was similarly increased. Three studies examined the association between paternal employment as a firefighter and the risk of cardiac birth defects. A case-control study considered 20 birth defect groups in 22,192 live births in British Columbia (Olshan et al. 1990). After adjustment for paternal age and race and maternal age, increased ORs were reported for paternal firefighting and ventricular septal defects (OR 2.7, 95% CI 1.02–7.18) and atrial septal defects (OR 5.91, 95% CI 1.60–21.83), compared with all other occupations. Increased ORs for both types of cardiac defects were also observed when firemen were compared with policemen. The second comparison group was selected to reduce potential confounding due to lifestyle factors and SES. Because the study relied on limited occupational information from birth registers, it was not possible to identify whether the firefighter fathers were urban or rural. However, the investigators tested whether there was any relationship between the year of a child’s birth and paternal employment as firefighter, hypothesizing that the risk of birth defects might have increased with increasing use of synthetic materials over the study period of 1952–1973. The findings suggest that paternal employment as a firefighter increases a child’s risk of being born with a ventricular or atrial septal defect. No specific information was available about duration of paternal firefighting and potential confounding factors beyond paternal age and race and maternal age. A cohort study of 836 infants of firefighters in Sweden was conducted (Kallen and Pradat 1992). There was no increased risk of cardiac defects (RR 0.93, 95% CI 0.38–1.92). Ventricular and atrial septal defects were examined separately, but no increased risk was found among infants fathered by firemen. The cohort, however, was relatively small and thus of limited statistical power. In a study of maternal or paternal exposure, Bates et al. (1997) studied all types of birth defects (ICD codes 40–759) in the offspring of parents living in Rotorua, New Zealand, a city with high geothermal exposure to hydrogen sulfide. No excess birth defects were reported in comparison with residents in the rest of New Zealand. The Bates studies were the only epidemiologic studies of H2S found by the committee that examined long-term health outcomes. Due to the paucity of literature, the committee did not make a separate conclusion on H2S.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence of an association between maternal and paternal combustion product exposure prior to conception or maternal exposure during early pregnancy and specific birth defects, including cardiac effects. Childhood Cancers Several childhood cancers have been investigated in relation to combustion-product exposure before birth (that is, before or during gestation): brain cancer, leukemia, and neuroblastoma. Each of those can arise from embryonic cells or poorly differentiated cells. Most studies of childhood cancer used case-control designs and examined cancer in relation to parental exposure. A California statewide, population-based cancer registry was used to identify cancers diagnosed in children who were less than 5 years old in 1988–1997 (Reynolds et al. 2004). The 4,369 cases were matched to 8,730 controls by birth date and sex. A mother’s residential address at the time of her child’s birth was used to calculate traffic density. For all cancer sites combined, the OR for the highest traffic-density exposure category compared with the lowest was 0.87 (95% CI 0.75–1.0). For all sites combined and for leukemia, the ORs were also below 1.0. For CNS tumors, the OR was 1.22 (CI 0.87–1.70). The authors found no increase in risk of cancer or leukemia among offspring of mothers living in high traffic density areas. Raaschou-Nielsen et al. (2001) studied 1,989 children in the Danish Cancer Registry who had leukemia, CNS tumors, or malignant lymphoma diagnosed during 1968–1991 and 5,506 randomly selected control children from the entire childhood population. Residential histories of cases and controls were traced from 9 months before birth until the time of diagnosis. Traffic patterns and concentrations of benzene and NO2 were calculated for the relevant period, and exposures to air pollution during pregnancy and during childhood were calculated separately. The risks of leukemia, CNS tumors, and all selected cancers combined were not linked to benzene or NO2, but the risk of lymphomas (specifically Hodgkin’s disease) increased by 25% (p for trend=0.06) and 51% (p for trend=0.05) with a doubling of the concentration of benzene and NO2, respectively during pregnancy. The authors note that traffic-related air pollution at the residence does not appear to be associated with leukemias, CNS tumors, or NHL in children. The Hodgkin’s disease finding was of borderline significance in univariate models and may be a chance finding or due to multiple testing. Results from the United Kingdom Childhood Cancer Study were analyzed (McKinney et al. 2003). Eligible cases were children who had a diagnosed malignant disease (including childhood leukemia, ALL, and brain cancer) or specified benign tumor. Cases were 0–14 years while a resident in England, Scotland, or Wales. Controls were randomly selected from the same family-health services in England and Wales and health boards in Scotland. There were 3,838 cases and 7,629 controls. Parents were interviewed to obtain an occupational history. Job titles and associated industries were coded according to the Standard Occupational Classification and Standard Industrial Classification of Economic Activities, respectively. The authors created 31 occupational groups by combining job titles considered to entail the same specific exposures. Timing of parental occupational exposure was also taken into account. When examining fathers occupationally exposed to combustion products at periconception, the authors found small increased risks for childhood leukemia and ALL. (Owing to substantial overlap between three occupational groups with “exhaust fumes” exposure, parents with some jobs may have been exposed to more than one of the agents and therefore included in more than one of the analyses.)

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 For ALL, paternal exposure to exhaust fumes at periconception had an OR of 1.26 (95% CI 1.02–1.56); exposure to inhaled particulate hydrocarbons, 1.41 (95% CI 1.11–1.79); and driving, 1.26 (95% CI 1.00–1.59). For leukemia, the ORs for paternal exposures were 1.33 (95% CI 1.09–1.61), 1.48 (95% CI 1.19–1.84), and 1.36 (95% CI 1.10–1.68), respectively. For CNS tumors, the ORs for paternal exposure to exhaust fumes and inhaled particulate hydrocarbons at periconception were 1.08 and 1.13, respectively, but the 95% CI included the null. For ALL, maternal exposure to exhaust fumes had an OR of 1.68 (95% CI 0.76–3.74); exposure to inhaled particulate hydrocarbons, 2.26 (95% CI 0.79–6.45); and driving, 1.74 (95% CI 0.63–4.85); but the 95% CIs included the null. The major limitations of this study are the nonspecific assessment of exposure based on occupation and the inability to account for other confounding exposures in the occupational groups. In addition, the creation of 31 occupational groups led to multiple comparisons and raised caution in interpreting the results. The strengths of the study include its size and population-based design. Vianna et al. (1984) conducted a case-control study of acute leukemia and neuroblastoma. Trained interviewers questioned the mother of each patient and control. Several control groups were used, including children chosen from birth certificates and matched to cases on several risk factors. The neuroblastoma cases were also used as a control group to explore whether the quality of information obtained from parents of children with leukemia and the parents of controls without a malignancy might differ, assuming that neuroblastoma did not share the risk factors of interest with leukemia. Exposure to aromatic hydrocarbons from gasoline exhaust was defined as working full-time in a specified occupation for at least a year before the birth of the child. The authors did not find an association between exposure to aromatic hydrocarbons and increased risk of neuroblastoma, but did report a higher risk of leukemia in patients whose fathers worked in high-exposure occupations (p=0.007). The primary study limitation is reliance on occupational groups to assign measures of exposure to combustion products. However, that limitation would most likely bias results toward the null. The relationship between parental occupation and leukemia and brain tumors in children was explored (Gold et al. 1982). A nonspecific measure of exposure to combustion products was used (motor-vehicle-related and including driver, motor-vehicle mechanic, service-station attendant, and railroad worker and engineer). There was an increased risk of leukemia in children whose fathers had vehicle-related occupations (p<0.05). No association was observed for brain cancer and vehicle-related occupations. The study is limited by the concurrent exposures to multiple agents in the fathers’ occupations. Cordier et al. (1997) conducted a population-based, case-control study of childhood brain tumors (251 cases and 601 controls) in three European centers. A Job-Exposure Matrix (JEM) was used to estimate parental occupational exposure to PAHs during the 5-year period before birth. Paternal occupation described as motor-vehicle-related had an OR of 1.6 (95% CI 1.0–2.8). The subset of cases with primitive neuroectodermal tumors had an OR of 2.7 (95% CI 1.1–6.6). They also described increased risks, although no dose-response relationship, with paternal exposure specifically to PAHs; the OR for medium exposure 1.8 (95% CI 1.2–2.6), and the OR for high exposure was 1.3 (95% CI 0.8–2.0). Maternal occupation was not associated with increased risk. The study limitations include the use of maternal recall to measure maternal and paternal occupations and the nonspecificity of jobs categorized as PAH-exposed. No association was found between childhood nervous system tumors and occupational groups broadly defined as hydrocarbon-related (Johnson et al. 1987). Another study (Hakulinen et al. 1976) found similar results in demonstrating no association between brain tumors,

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 leukemia, and lymphoma and paternal occupations described nonspecifically as hydrocarbon-related. A case-control study of childhood leukemia and parental occupation did not find an increased risk with occupational exposure to exhaust gases (van Steensel-Moll et al. 1985), and another study (Zack et al. 1980) found no association between leukemia or lymphoma and paternal occupation as a motor-vehicle mechanic or service-station attendant. A study examining neuroblastoma and numerous paternal occupations, including firefighter and motor-vehicle operator, also found no increased risk (Olshan et al. 1999). All the studies were limited by their inability to validate employment history. They also lacked details on specific assessment of exposure to combustion products. The broad exposure groups included many diverse occupations with exposure to other chemicals in addition to combustion products. In addition, the studies should be viewed cautiously because many of them conducted multiple comparisons. They are best used to generate hypotheses that require more precise assessment of exposure to combustion products. The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence of an association between parental combustion product exposure and all childhood cancers studied, including acute lymphocytic leukemia, leukemia, neuroblastoma, and brain cancer. REFERENCES ACS (American Cancer Society). 1999. Childhood Cancer—General Statement. [Online]. Available: http://www.cancer.org/downloads/CRI/Childhood%20Cancer%20%-20General%20Statement%20_PDF_.pdf [accessed February 21, 2002]. ACS. 2002a. ACS: Brain and Spinal Cord Tumors in Children. [Online]. Available: http://www.cancer.org/downloads/CRI/Brain%20and%20Spinal%20Cord%20Tumors%20in%20Children%20_PDF_.pdf [accessed February 21, 2002]. ACS. 2002b. Childhood Leukemia. [Online]. Available: http://www.cancer.org/downloads/CRI/Childhood%20Leukemia%20_PDF_.pdf [accessed February 21, 2002]. Akefeldt A, Anvret M, Grandell U, Nordlinder R, Gillberg C. 1995. Parental exposure to hydrocarbons in Prader-Willi syndrome. Developmental Medicine and Child Neurology 37(12):1101–1109. Araneta MR, Kamens DR, Zau AC, Gastanaga VM, Schlangen KM, Hiliopoulos KM, Gray GC. 2004. Conception and pregnancy during the Persian Gulf War: The risk to women veterans. Annals of Epidemiology 14(2):109–116. Araneta MR, Moore CA, Olney RS, Edmonds LD, Karcher JA, McDonough C, Hiliopoulos KM, Schlangen KM, Gray GC. 1997. Goldenhar syndrome among infants born in military hospitals to Gulf War veterans. Teratology 56(4):244–251. Araneta MR, Schlangen KM, Edmonds LD, Destiche DA, Merz RD, Hobbs CA, Flood TJ, Harris JA, Krishnamurti D, Gray GC. 2003. Prevalence of birth defects among infants of Gulf War veterans in Arkansas, Arizona, California, Georgia, Hawaii, and Iowa, 1989–1993. Birth Defects Research Part A: Clinical and Molecular Teratology 67(4):246–260. Bates MN, Garrett N, Graham B, Read D. 1997. Air pollution and mortality in the Rotorua geothermal area. Australian and New Zealand Journal of Public Health 21(6):581–586. Bobak M, Leon DA. 1999. Pregnancy outcomes and outdoor air pollution: An ecological study in districts of the Czech Republic 1986–8. Occupational and Environmental Medicine 56(8):539–543. Bobak M. 2000. Outdoor air pollution, low birth weight, and prematurity. Environmental Health Perspectives 108(2):173–176.

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