Gulf War and Health Volume 11: Generational Health Effects of Serving in the Gulf War (2018) / Chapter Skim
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7 Solvents
7 Solvents
Pages 317-396
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From page 317... ...
The Volume 2 committee identified a large number of solvents sent to the Gulf War (see Appendix D in Volume 2) , many of which have been extensively studied.
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From page 318... ...
X Ethylene glycol X X X R (E) X monoethyl ether Ethylene glycol X X X X monomethyl ether Ethyl ether*
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From page 319... ...
X Propylene glycol X X monoethyl ether Propylene glycol X X X monomethyl ether NOTES: kL=kiloliter; OSAGWI=Office of the Special Assistant for Gulf War Illnesses. a These solvents were reviewed by the Volume 2 committee (IOM, 2003)
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From page 320... ...
Although the Volume 2 committee reached conclusions on the category of association for specific solvents and most reproductive and developmental health outcomes (e.g., that there was evidence of a causal association between benzene exposure and acute leukemia in adults) , it was unable to reach a consensus on the category of association for parental preconception exposure to solvents and the developmental health effect of childhood leukemia.
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From page 321... ...
. The risk of spontaneous abortion was not significantly increased with low-level benzene exposures (concentrations not measured)
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. However, female workers in the Chinese petrochemical industry exposed to undefined levels of benzene had a significantly increased risk of spontaneous abortion (RR=2.5, 95% CI 1.7–3.7)
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From page 323... ...
The authors used birth certificate information to identify mothers at delivery and groundwater modeling to estimate solvent concentrations. The esearchers r found no association between residential prenatal exposure to any concentration of benzene during the entire pregnancy and the risk of a small for gestational age infant, preterm birth, reduced mean birth weight, or full-term low birth weight.
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From page 324... ...
at concentrations that also cause maternal toxicity. ATSDR concluded that there was limited evidence from animal studies that oral exposure to benzene affects reproductive organs and that there was no information on the reproductive effects from inhalation exposure.
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From page 325... ...
. Maternal and paternal occupational exposure to benzene were both significantly associated with an increased risk (sRR=1.71, 95% CI 1.14–2.58; 7 studies, and sRR=1.18, 95% CI 1.00–1.41; 6 studies, respectively)
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From page 326... ...
Birth certificates were used to identify the 51 cases and 526 control parent–child pairs. Prenatal benzene exposure in the first trimester, dichotomized to exposed/unexposed, was not significantly associated with an increased risk of childhood leukemia or non-Hodgkin's lymphoma or oral cleft defects.
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From page 327... ...
included numerous animal studies that reported that inhalation exposure to benzene produced fetotoxicity as evidenced by decreased body weight and by increased skeletal variants such as missing sternebrae and extra ribs, although ATSDR did not consider these to be malformations, but rather the result of maternal toxicity. Alterations in hematopoiesis was also observed in the fetuses and offspring of pregnant mice exposed via inhalation to low levels of benzene.
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From page 328... ...
Studies of the effects of prenatal exposure to benzene have generally been done by measuring its concentrations in ambient air -- frequently by comparing maternal exposures at residences near roads versus residences further from obvious benzene sources. Reproductive Effects The effects of benzene exposure on male reproduction have been studied in occupational settings, primarily in China.
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From page 329... ...
. The 2015 Addendum to the ATSDR Toxicological Profile, after an evaluation of numerous epidemiological studies on developmental effects following maternal exposure to benzene in ambient air, found that there was a significant increase in the risk of spina bifida but not anencephaly or cleft lip with or without cleft palate (ATSDR, 2015a)
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From page 330... ...
(2013) of children born to mothers who had resided at Camp Lejeune, North Carolina, found that first-trimester exposure to drinking water contaminated with benzene significantly increased the risk of neural tube defects.
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33 exposed men (17 with low containing glues versus working in a Occupational exposures to benzene were associated benzene exposures and 16 with meat packing plant; personal passive with increased frequencies of aneuploid sperm for high exposures) compared with air badges were used for 2 days, chromosomes X, Y, or 21; significant exposure 33 nonexposed male workers in and urine spot samples were used to dependent increases in the frequencies of sperm Tianjin, China.
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From page 332... ...
, high exposure drinking water at Marine Corps low birth weight, and birth weight; OR=0.8 (95% CI 0.6–1.1) ; term low birth weight base Camp Lejeune during 1968– for preterm exposure stratified to low exposure OR=1.0 (95% CI 0.8–1.4)
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6 cases of neural tube defects, Camp Lejeune during first trimester NTD: OR=4.1, 95% CI 1.4–12.0; 3 cases of oral clefts, 2 cases of pregnancy (exposed versus Oral cleft defect: OR=0.7, 95% CI 0.2–2.2; of leukemia or non-Hodgkin's unexposed; actual benzene levels Childhood leukemia or non-Hodgkin's lymphoma: lymphoma versus health controls in contaminated drinking water not OR=0.8, 95% CI 0.2–3.8. born during 1968–1985 to given)
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(2016) and household product exposures occupational and household use of Pooled estimate for all childhood leukemia and any to benzene and risk of childhood benzene and solvents, traffic density, benzene exposure RR=1.96 (95% CI 1.53–2.52; leukemia completed during and traffic-related air pollution.
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. Exposure increased risk of ALL (OR=1.07, 95% CI 0.43– versus parents of healthy children levels not defined.
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. Analysis of prenatal benzene exposure combined with NO2 exposure resulted in negative, nonsignificant associations with mental and motor scores.
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Epidemiologic studies on the reproductive and developmental effects of toluene reviewed below are summarized in Table 7-3 at the end of this section. Reproductive Effects Reproductive Effects in Men The Volume 2 committee identified several studies that examined the effects of toluene exposure on male infertility.
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reviewed three studies not included in Gulf War and Health, Volume 2 on the occurrence of spontaneous abortion in women exposed to toluene (Lindbohm et al., 1991; Ng et al., 1992; Taskinen et al., 1989)
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The Volume 11 committee did not identify any additional animal studies on the possible reproductive effects of toluene in male or female animals. Developmental Effects Several developmental endpoints have been studied following parental exposure to toluene -- specifically childhood cancers and several types of birth defects -- and were reported in Volume 2, by ATSDR, and by the Volume 11 committee in this volume.
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From page 340... ...
Toluene exposure at 3 months before pregnancy for painters was predicted to range from 0.17 to 4.66 mg/m3, which was below the occupational exposure limit of 150 mg/m3 in the Netherlands. Compared with carpenters, painters with occupational exposure in the 3 months before pregnancy did have a significantly increased risk of birth defects in offspring (OR=2.4, 95% CI 1.2–4.9)
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From page 341... ...
. Animal Studies There were no toxicological or animal studies of possible developmental effects of toluene exposure cited in Gulf War and Health, Volume 2.
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found that the data did not provide convincing evidence that acute or repeated inhalation exposure to toluene caused reproductive effects in humans. ATSDR presented limited evidence in humans to indicate that occupational exposure to toluene may lead to an increased incidence of spontaneous abortion (Lindbohm et al., 1991; Ng et al., 1992; Taskinen et al., 1989)
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From page 343... ...
A dose–response relationship (p-trend=0.03) was observed for all birth defects (low OR=2.1, 95% CI 0.7–5.9; intermediate OR=3.0, 95% CI 1.3–7.0; high OR=2.2, 95% CI 0.8–6.0)
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From page 344... ...
Heck et al. Case-control Exposure estimated based on residence Childhood leukemia.
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Epidemiologic studies on the reproductive and developmental effects of xylenes reviewed below are summarized in Table 7-4 at the end of this section. Reproductive Effects Reproductive Effects in Men and Women The Volume 2 committee (IOM, 2003)
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From page 346... ...
Animal Studies ATSDR (2007b) found no reproductive effects in rats exposed via inhalation to 500 ppm xylene before mating and during gestation and lactation.
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From page 347... ...
(2011) assessed the risk for neural tube defects, expressed in the form of spina bifida or anencephaly, as a result of prenatal exposure to ambient air pollutants in a population-based study in Texas.
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From page 348... ...
The Volume 11 committee concludes that there is inadequate/insufficient evidence to determine whether an association exists between exposure to xylenes and reproductive effects in men or women, or with adverse pregnancy outcomes. Developmental Effects One study suggested that BTEX exposure may increase the risk of low birth weight for gestational age, although the effect size was small.
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(2013) 3,945 cases of oral clefts exposure based on maternal Cleft lip with or without cleft palate: High versus low from the Texas Birth Defects residence at delivery modeled exposure OR=0.93, 95% CI 0.80–1.10.
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From page 350... ...
pregnant mothers in in maternal residence with passive associated with increased levels of miR-223 or miR-155 prospective mother–child monitor; median concentrations in maternal blood or cord blood. study in Germany (Lifestyle for the m-+p-isomers was 1.55 and Environmental Factors μg/m3 and the o-isomer was 0.49 and Their Influence on μg/m3.
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From page 351... ...
Reproductive Effects The potential reproductive effects of TCE have been studied by numerous researchers and have been evaluated by several organizations, including the NRC, EPA, and ATSDR. The 2009 NRC report on PCE- and TCE-contaminated drinking water at Camp Lejeune found limited suggestive evidence of an association between TCE, PCE, or solvent mixtures and female infertility; however, there was inadequate/insufficient evidence to determine whether an association existed between exposure to TCE, PCE, or solvent mixtures and female infertility after the exposure ceased; between maternal or paternal preconception exposure and miscarriage, preterm birth, or fetal growth restriction; or between prenatal exposure and preterm birth or fetal growth restriction (NRC, 2009)
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From page 352... ...
Adverse Pregnancy Outcomes Volume 2 included a study of Finnish women with occupational exposures to TCE that showed an increased risk of spontaneous abortion (OR=2.2, 95% CI 1.2–4.1) (Lindbohm et al., 1990)
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From page 353... ...
The results were mixed for an increased risk of spontaneous abortion, and some studies found that prenatal maternal exposures to TCE were associated with lower birth weights. The Volume 11 committee considered two additional studies.
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In the 2014 ATSDR review, animal studies supported the epidemiologic findings of reduced fertility and adverse birth outcomes, although only when the animals received repeated high doses of TCE. The only study of female rats found no reproductive effects following preconception exposure.
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. EPA found that both human and animal studies indicated that a number of congenital malformations were associated with prenatal maternal environmental and occupational exposure to TCE; these exposures were via inhalation and consumption of contaminated drinking water.
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From page 356... ...
(2012) study, cited under Reproductive Effects, children born to women with inhalation exposure to TCE as a result of soil-vapor intrusion were found to be at a significantly increased risk of cardiac defects (RR=2.15, 95% CI 1.27–3.62)
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From page 357... ...
A oneinterquartile increase in TCE concentrations did not increase the risk for ALL during the first, second, or third trimester or during the entire pregnancy, nor the risk of AML at any time during the pregnancy. In the NORD-TEST study described in the benzene section, there was no increased risk of testicular germ cell tumors in men aged 14–49 years relative to their parents exposures to TCE in the year prior to their birth in Finland, Norway, and Sweden (OR=0.98, 95% CI 0.62–1.54 and OR=1.10, 95% CI 0.94–1.28, for maternal and paternal occupational exposures, respectively)
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From page 358... ...
Most of the studies reviewed by NRC, EPA, and ATSDR have found prenatal exposure to TCE to be associated with a number of adverse pregnancy outcomes, particularly an increased risk of spontaneous abortion and decreased birth weight. Most of the studies were small in size, and the exposures were usually to a mixture of solvents, although some studies did make efforts to isolate exposure to specific solvents, including TCE.
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From page 359... ...
However, the study of TCE-contaminated drinking water at Camp Lejeune did not find any increased risk for neural tube or oral cleft defects. The most studied birth defects are those of the cardiovascular system.
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From page 360... ...
Developmental Effects Forand et al. Cohort Estimated for maternal residence at Birth defects.
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From page 361... ...
Ruckart et al. Case-control Exposure during the 1st trimester Birth defects (neural tube or oral cleft defects)
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From page 362... ...
(2015) 533 cases of spina bifida from maternal residence at birth and Medium exposure level OR=2.00, 95% CI 1.14–3.61, the Texas Birth Defects Registry census tract-level estimates of Bayes factor=3.79; high exposure level OR=1.32, 95% CI versus 3,695 controls selected air pollutants obtained from the 0.61–2.80, Bayes factor=0.60.
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. In its assessment of the reproductive and developmental effects of PCE, the Volume 11 commit tee considered four earlier, comprehensive reports -- Gulf War and Health, Volume 2 (IOM, 2003)
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found a nonsignificant increased risk of spontaneous abortion (OR=1.1, 95% CI 0.6–2.0) in a study of women working in laundry or dry cleaning facilities in Sweden who had exposures during the first trimester.
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EPA found that "Overall, no associations were noted in several studies that assessed maternal or paternal occupational exposure to PCE and increased incidence of stillbirths, congenital anomalies, or decreased birth weight (Lindbohm, 1995; Windham et al., 1991; Olsen et al., 1990; Kyyronen et al., 1989; Taskinen et al., 1989; Bosco et al., 1987) ." The 2014 ATSDR Draft Toxicological Profile for Tetrachloroethylene also assessed many of the studies reviewed by the IOM, NRC, and EPA.
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From page 366... ...
Decreased fetal and maternal weight were observed in rats and mice exposed to concentrations of 300–664 ppm during gestation. The Volume 11 committee did not identify any new animal studies on the reproductive effects of PCE.
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; among offspring with any prenatal exposure, the OR for neural tube defects was 3.5 (95% CI 0.8–14.0) and for oral clefts was 3.2 (95% CI 0.7–15.0)
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From page 368... ...
; however, when the exposures were dichotomized to exposed/unexposed, there was no increased risk. Exposure to PCE at any level was not associated with a significantly increased risk of oral cleft defects or childhood leukemia or non-Hodgkin's lymphoma.
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From page 369... ...
Although some studies in Scandinavian populations suggest that maternal occupational exposure to PCE may increase the risk of spontaneous abortion, studies in a Massachusetts residential population found no association between PCE in drinking water and spontaneous abortion, birth weight, or gestational age.
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From page 370... ...
The Volume 11 committee finds that there is inadequate/insufficient evidence to determine whether an association exists between exposure to PCE and reproductive effects in men or women, or with adverse pregnancy outcomes. Developmental Effects Numerous researchers have assessed the effects of prenatal exposure, primarily maternal, on developmental effects, including childhood cancers, birth defects, and neurodevelopmental deficits.
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Ruckart et al. Cohort -- 11,896 PCE-contaminated drinking water at Adverse pregnancy outcomes (PTB, SGA, LBW, mean birth weight (2014)
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Aschengrau et al. Cohort -- Cape Cod, PCE-contaminated drinking water in Adult health assessed by questionnaire.
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(2016) 201,559 children estimated from census tract for Children with high exposures to both diesel PM and PCE had born between 1994 residence at birth and EPA's 1996 greater risk of failing to meet test-based standards for mathematics and 1998 who National Air Toxics Assessment.
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Nested case-control PCE-contaminated drinking water at Birth defects and childhood cancers with medical confirmation.
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EGBE Propylene glycol monomethyl ether PGME Diethylene glycol monobutyl ether DEGBE
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From page 376... ...
. Male and female workers in the semiconductor industry are known to be exposed to ethylene glycol ethers.
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From page 377... ...
The risk of spontaneous abortion was significantly increased for fabrication workers with the greatest predicted exposure to ethylene glycol ether (RR=2.67, 95% CI 1.33–5.36) , and there was no increase associated with exposure to propylene glycol ether.
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From page 378... ...
The Volume 11 committee considered 13 animal studies on the male reproductive effects of a variety of ethylene glycols and glycol ethers, particularly EGME. In 2- and 13-week repeat-dose oral toxicity studies in rats, Johnson et al.
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From page 379... ...
reported that in rats exposed to propylene glycol in drinking water there were no adverse effects on any measure of reproduction, including the number of litters, litter size, pup weight, or sex ratio, even at the highest dose, nor was there any effect on the reproductive capacity of the offspring from the high-dose group. Some female rats and rabbits that breathed in large amounts of EGBE while they were pregnant delivered fewer offspring than pregnant rats or rabbits that were not exposed; the doses also produced maternal toxicity.
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From page 380... ...
The Volume 11 committee identified several new studies on the effects of glycol ethers or ethylene glycols on female reproduction in animal models. The reproductive toxicity of diethylene glycol (DEG)
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From page 381... ...
ATSDR (2010) reviewed several animal studies on the developmental toxicity of ethylene glycol via inhalation, oral, and dermal exposures in acute-duration studies and by oral exposure in intermediateduration studies.
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From page 382... ...
ATSDR found that the developmental effects of intermediate-duration oral exposure to ethylene glycol included kidney effects in offspring. The Volume 11 committee reviewed the findings of developmental toxicity studies of several ethylene glycols and glycol ethers not cited by ATSDR.
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From page 383... ...
Developmental Effects The Volume 11 committee considered four studies that evaluated congenital malformations associated with preconception or periconception exposure to glycol ethers, with inconsistent results. Two studies found that maternal exposure to glycol ethers in the first trimester of pregnancy significantly increased the risk of having a child with a neural tube defect, spina bifida, or other birth defects such as cleft palate (Cordier et al., 1997; Lorente et al., 2000)
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From page 384... ...
A review of the toxicity of ethylene glycols indicated that they are unlikely to be reproductive toxicants or to be embryotoxic in humans at "environmentally relevant doses" and that they do not cause developmental effects at doses that do not cause significant maternal toxicity (Fowles et al., 2017)
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From page 385... ...
(2007) 98 men employed at the about occupational exposure to glycol ethers BAA and 2-MPA not correlated with any semen Paris Municipality during for the past 10 years and urinary metabolites, parameters or hormone levels.
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From page 386... ...
. NOTE: BAA=butoxyacetic acid; CI=confidence interval; EAA=ethoxyacetic acid; EEAA=ethoxy ethoxyacetic acid; EGME=ethylene glycol monomethyl ether (2-methoxyethanol)
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From page 387... ...
2010. Toxicological profile for ethylene glycol.
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2005. Developmental toxicity study with diethylene glycol dosed by gavage to CD rats and CD-1 mice.
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From page 389... ...
11) Two- or four-week repeated-dose studies and fertility study of ethylene glycol monomethyl ether in female rats.
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From page 390... ...
2011. MicroRNAs expression in the ethylene glycol monomethyl ether-induced testicular lesion.
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From page 391... ...
2005. Diethylene glycol monobutyl ether (DGBE)
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From page 392... ...
2018. Transcriptional profile of ethylene glycol monomethyl ether-induced testicular toxicity in rats.
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From page 393... ...
2013. Evaluation of exposure to contaminated drinking water and specific birth defects and childhood cancers at Marine Corps Base Camp Lejeune, North Carolina: A case-control study.
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From page 394... ...
2015. MicroRNA profiling in ethylene glycol monomethyl ether–induced monkey testicular toxicity model.
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From page 395... ...
. Repeated toxicity study on ethylene glycol monomethyl ether for 2 and 4 weeks to detect effects on male reproductive organs in rats.
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From page 396... ...
1990. Reproductive effects of diethylene glycol and diethylene glycol monoethyl ether in Swiss CD-1 mice assessed by a continuous breeding protocol.
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