Determination of Presumption of Service Connection Concerning Illnesses Discussed in National Academy of Sciences Report on Gulf War and Health, 50856-50869 [E8-19971]

Agencies

• DEPARTMENT OF VETERANS AFFAIRS

[Federal Register Volume 73, Number 168 (Thursday, August 28, 2008)]
[Notices]
[Pages 50856-50869]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E8-19971]


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DEPARTMENT OF VETERANS AFFAIRS


Determination of Presumption of Service Connection Concerning 
Illnesses Discussed in National Academy of Sciences Report on Gulf War 
and Health

AGENCY: Department of Veterans Affairs.

ACTION: Notice.

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SUMMARY: As required by law, the Department of Veterans Affairs (VA) 
hereby gives notice that the Secretary of Veterans Affairs, under the 
authority granted by the Persian Gulf War Veterans Act of 1998, Public 
Law 105-277, title XVI, 112 Stat. 2681-742 through 2681-749 (codified 
in part at 38 U.S.C. 1118), has determined that there is no basis to 
establish a presumption of service connection at this time for any of 
the diseases, illnesses, or health effects discussed in the December 
20, 2004, report of the National Academy of Science, titled ``Gulf War 
and Health, Volume 3. Fuels, Combustion Products, and Propellants'' 
based on exposure to fuels, combustion products, or propellants during 
service in the Persian Gulf during the Persian Gulf War. This 
determination does not in any way preclude VA from granting service 
connection for any disease, including those specifically discussed in 
this notice, nor does it change any existing rights or procedures.

FOR FURTHER INFORMATION CONTACT: Rhonda F. Ford, Chief, Regulations 
Staff (211D), Compensation and Pension Service, Veterans Benefits 
Administration, Department of Veterans Affairs, 810 Vermont Avenue, 
NW., Washington, DC 20420, (202) 461-9739.

SUPPLEMENTARY INFORMATION:

I. Statutory Requirements

    The Persian Gulf War Veterans Act of 1998, Public Law 105-277, 
title XVI, 112 Stat. 2681-742 through 2681-749 (codified at 38 U.S.C. 
1118), and the Veterans Programs Enhancement Act of 1998, Public Law 
105-368, 112 Stat. 3315, directed the Secretary to seek to enter into 
an agreement with the National Academy of Sciences (NAS) to review and 
evaluate the available scientific evidence regarding associations 
between illnesses and exposure to toxic agents, environmental or 
wartime hazards, or preventive medicines or vaccines to which service 
members may have been exposed during service in the Persian Gulf during 
the Gulf War. Congress directed NAS to identify agents, hazards, 
medicines, and vaccines to which service members may have been exposed 
during service in the Persian Gulf during the Gulf War.
    Congress mandated that NAS determine, to the extent possible: (1) 
Whether there is a statistical association between exposure to the 
agent, hazard, medicine, or vaccine and the illness, taking into 
account the strength of the scientific evidence and the appropriateness 
of the scientific methodology used to detect the association; (2) the 
increased risk of illness among individuals exposed to the agent, 
hazard, medicine, or vaccine; and (3) whether a plausible biological 
mechanism or other evidence of a causal relationship exists between 
exposure to the agent, hazard, medicine, or vaccine and the illness.
    Section 1118 provides that whenever the Secretary determines, based 
on sound medical and scientific evidence, that a positive association 
(i.e., the credible evidence for the association is equal to or 
outweighs the credible evidence against the association) exists between 
exposure of humans or animals to a biological, chemical, or other toxic 
agent, environmental or wartime hazard, or preventive medicine or 
vaccine known or presumed to be associated with service in the 
Southwest Asia theater of operations during the Persian Gulf War and 
the occurrence of a diagnosed or undiagnosed illness in humans or 
animals, the Secretary will publish regulations establishing 
presumptive service connection for that illness. If the Secretary 
determines that a presumption of service connection is not warranted, 
the Secretary is to publish a notice of that determination, including 
an explanation of the scientific basis for that determination. The 
Secretary's determination must be based on consideration of the NAS 
reports and all other sound medical and scientific information and 
analysis available to the Secretary.
    Although section 1118 does not define ``credible evidence,'' it 
does instruct the Secretary to take into consideration whether the 
results (of any report, information, or analysis) are statistically 
significant, are capable or replication, and withstand peer review. See 
38 U.S.C. 1118(b)(2)B). Simply comparing the number of studies that 
report a significantly increased relative risk to the number of studies 
that report a relative risk that is not significantly increased is not 
a valid method for

[[Page 50857]]

determining whether the weight of evidence overall supports a finding 
that there is or is not a positive association between exposure to an 
agent, hazard, or medicine or vaccine and the subsequent development of 
the particular illness. Because of differences in statistical 
significance, confidence levels, control for confounding factors, and 
other pertinent characteristics, some studies are clearly more credible 
than others, and the Secretary has given the more credible studies more 
weight in evaluating the overall weight of the evidence concerning 
specific illnesses.

II. Prior National Academy of Sciences Reports

    NAS issued its initial report titled, Gulf War and Health, Volume 
1: ``Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines,'' on 
January 1, 2000. In that report, NAS limited its analysis to the health 
effects of depleted uranium, the chemical warfare agent sarin, 
vaccinations against botulism toxin and anthrax, and pyridostigmine 
bromide, which was used in the Gulf War as a pretreatment for possible 
exposure to nerve agents. On July 6, 2001, VA published a notice in the 
Federal Register announcing the Secretary's determination that the 
available evidence did not warrant a presumption of service connection 
for any disease discussed in that report. See 66 FR 35702 (2001).
    NAS issued its second report titled, ``Gulf War and Health, Volume 
2: Insecticides and Solvents,'' on February 18, 2003. In that report, 
NAS focused on the health effects of insecticides and solvents that 
were shipped to the Persian Gulf during the Persian Gulf War. The 
pesticides considered by NAS were organophosphorous compounds 
(malathion, diazinon, chlorpyrifos, dichlorvos, and azamethiphos), 
carbamates (carbaryl, propoxur, and methomyl), pyrethrins and 
pyrethyroids (permethrin and d-phenothrin), lindane, and N,N-diethyl-3-
methylbenzamide (DEET). NAS considered 53 solvents in eight groups: 
Aromatic hydrocarbons (including benzene), halogenated hydrocarbons 
(including tetrachloroethylene and dry-cleaning solvents), alcohols, 
glycols, glycol esters, esters, ketones, and petroleum distillates. On 
August 24, 2007, VA published a notice in the Federal Register 
announcing the Secretary's determination that the available evidence 
did not warrant a presumption of service connection for any disease 
discussed in that report. 72 FR 48734 (2007).

III. Gulf War and Health, Volume 3. Fuels, Combustion Products, and 
Propellants

    NAS issued a third report, titled ``Gulf War and Health, Volume 3. 
Fuels, Combustion Products, and Propellants,'' on December 20, 2004. In 
that report, NAS focused on the health effects of hydrazines, red 
fuming nitric acid, hydrogen sulfide, oil-fire byproducts, diesel-
heater fumes, and fuels (for example, jet fuel and gasoline).
    In its report, NAS classified the evidence of an association 
between exposure to a specific agent and a specific health outcome into 
five categories:
     Sufficient Evidence of a Causal Association: This category 
means the evidence is sufficient to conclude that there is a causal 
association between exposure to a specific agent and a specific health 
outcome in humans. The evidence is supported by experimental data and 
fulfills the guidelines for sufficient evidence of an association. The 
evidence must be biologically plausible and satisfy several of the 
guidelines used to assess causality, such as: Strength of association, 
dose-response relationship, consistency of association, and a temporal 
relationship.
    NAS did not find any health outcomes that met the criteria for this 
category.
     Sufficient Evidence of an Association: This category means 
the evidence is sufficient to conclude that a consistent association 
has been observed between exposure to a specific agent and a specific 
health outcome in human studies in which chance and bias, including 
confounding, could be ruled out with reasonable confidence. For 
example, several high-quality studies report consistent associations, 
and the studies are sufficiently free of bias, including adequate 
control for confounding.
    NAS found sufficient evidence of an association between exposure to 
combustion products and lung cancer.
     Limited/Suggestive Evidence of an Association: This 
category means the evidence is suggestive of an association between 
exposure to a specific agent and a specific health outcome, but the 
body of evidence is limited by the inability to rule out chance and 
bias, including confounding, with confidence. For example, at least one 
high-quality study reports an association that is sufficiently free of 
bias, including adequate control for confounding. Other corroborating 
studies provide support for the association, but they were not 
sufficiently free of bias, including confounding. Alternatively, 
several studies of lower quality show consistent associations, and the 
results are probably not due to bias, including confounding.
    NAS found limited/suggestive evidence of an association between 
exposure to combustion products and cancers of the nasal cavity and 
nasopharynx; cancers of the oral cavity and oropharynx; laryngeal 
cancer; bladder cancer; low birthweight/intrauterine growth retardation 
(with exposure during pregnancy); preterm birth (with exposure during 
pregnancy); and incident asthma.
    NAS found limited/suggestive evidence of an association between 
exposure to hydrazines and lung cancer.
     Inadequate/Insufficient Evidence: This category means the 
evidence is of insufficient quantity, quality, or consistency to permit 
a conclusion regarding the existence of an association between exposure 
to a specific agent and a specific health outcome in humans.
    NAS found inadequate/insufficient evidence of an association 
between exposure to fuels and cancers of the oral cavity and 
oropharynx; cancers of the nasal cavity and nasopharynx; esophageal 
cancer; stomach cancer; colon cancer; rectal cancer; hepatic cancer; 
pancreatic cancer; laryngeal cancer; lung cancer; melanoma; nonmelanoma 
skin cancer; female breast cancer; male breast cancer; female genital 
cancers (cervical, endometrial, uterine, and ovarian cancers); 
prostatic cancer; testicular cancer; nervous system cancers; kidney 
cancer; bladder cancer; Hodgkin's disease; non-Hodgkin's lymphoma; 
multiple myeloma; myelodysplastic syndromes; adverse reproductive or 
developmental outcomes (including infertility, spontaneous abortion, 
childhood leukemia, central nervous system (CNS) tumors, neuroblastoma, 
and Prader-Willi syndrome); peripheral neuropathy; neurobehavioral 
effects; Multiple Chemical Sensitivity symptoms; nonmalignant 
respiratory disease; chronic bronchitis; asthma; emphysema; dermatitis 
(irritant and allergic); and sarcoidosis.
    NAS found inadequate/insufficient evidence of an association 
between exposure to combustion products and esophageal cancer; stomach 
cancer; colon cancer; rectal cancer; hepatic cancer; pancreatic cancer; 
melanoma; female breast cancer; male breast cancer; female genital 
cancers (cervical, endometrial, uterine, and ovarian cancers); 
prostatic cancer; testicular cancer; nervous system cancers; ocular 
melanoma; kidney cancer; non-

[[Page 50858]]

Hodgkin's lymphoma; Hodgkin's disease; multiple myeloma, leukemia; 
myelodysplastic syndromes; preterm births (based on exposure during a 
specific time period during pregnancy, such as the first trimester); 
low birth weight and intrauterine growth retardation (based on exposure 
before gestation or during a specific period during pregnancy, such as 
the first trimester); specific birth defects, including cardiac effects 
(with maternal or paternal exposure before conception or maternal 
exposure during early pregnancy); all childhood cancers identified, 
including acute lymphocytic leukemia, leukemia, neuroblastoma, and 
brain cancer; neurobehavioral effects; post-traumatic stress disorder; 
nervous system subgroupings (or individual nervous system diseases); 
Multiple Chemical Sensitivity symptoms; chronic bronchitis (less than 1 
year of exposure); emphysema; chronic obstructive pulmonary disease; 
ischemic heart disease or myocardial infarction (less than 2 years of 
exposure); dermatitis (irritant and allergic); and sarcoidosis.
    NAS found inadequate/insufficient evidence of an association 
between exposure to hydrazines and hematopoietic and lymphopoietic 
cancers; digestive tract cancers; pancreatic cancer; bladder cancer; 
kidney cancer; emphysema; ischemic heart disease or myocardial 
infarction; and hepatic disease.
    NAS found inadequate/insufficient evidence of an association 
between exposure to nitric acid and stomach cancer; melanoma; 
lymphopoietic cancers; pancreatic cancer; laryngeal cancer; lung 
cancer; bladder cancer; multiple myeloma; and cardiovascular diseases.
     Limited/Suggestive Evidence of No Association: This 
category means the evidence is consistent in not showing an association 
between exposure to a specific agent and a specific health outcome 
after exposure of any magnitude. A conclusion of no association is 
inevitably limited to the conditions, magnitudes of exposure, and 
length of observation in the available studies. The possibility of a 
very small increase in risk after exposure studied cannot be excluded.
    NAS did not find any health outcomes that met the criteria for this 
category.

A. Combustion Products

1. Sufficient Evidence of an Association
    NAS found sufficient evidence of an association between combustion 
products and lung cancer. NAS found that there was evidence of 
associations between exposure to ambient air pollution, engine 
exhausts, and heating sources (coal) and lung cancer. Cohort and case-
control studies showed consistently that risks increased with 
increasing ambient air pollution. There was evidence from both cohort 
and case control studies that increasing exposure to engine exhausts 
and its components such as polycyclic aromatic hydrocarbons (PAHs) 
increased the risk of lung cancer.
    Based on 82 epidemiological studies, NAS derived a positive finding 
of ``sufficient evidence of an association'' between exposure to 
combustion products and lung cancer. The epidemiological studies 
included cohort studies on the health effects of ambient air pollution 
on people dwelling in cities, workers exposed to motor vehicle exhaust, 
and case-control studies of lung cancer patients. The case-control 
studies were of lung cancer patients who were exposed in their 
occupation, or in their homes or daily lives to indoor air pollution 
from combustion products from wood, coal, kerosene or gas burning 
stoves or heaters over years. Relevant occupational exposures included 
working as a bus, taxi, or truck driver, or as a miner or railroad 
worker.
    NAS pointed out that lung cancer from all causes is the leading 
cause of cancer death among both men and women, and that smoking may be 
responsible for 80% of lung cancer cases. Nevertheless, NAS concluded 
that ``there was evidence of associations between exposure to ambient 
air pollution, engine exhausts, and heating sources (coal) and lung 
cancer.'' Cohort and case-control studies showed consistently that 
risks increased with increasing ambient air pollution. There was 
evidence from both cohort and case-control studies that increasing 
exposure to engine exhausts and to its components increased the risk of 
lung cancer.
    The Secretary has determined that, although there is sufficient 
evidence of an association between combustion products and lung cancer, 
VA does not consider this exposure to be ``associated with'' the 1991 
Gulf War. Please see section IV for further detail.
2. Limited/Suggestive Evidence of an Association
    NAS found limited/suggestive evidence of an association between 
exposure to combustion products and cancers of the nasal cavity and 
nasopharynx; cancers of the oral cavity and oropharynx; laryngeal 
cancer; bladder cancer; low birthweight/intrauterine growth retardation 
and exposure during pregnancy; preterm birth and exposure during 
pregnancy; and incident asthma.
    The results of the studies of the relationship between combustion 
products and cancers of the nasal cavity and nasopharynx were 
inconsistent, and indirect methods were used to assess exposure. 
However, positive associations were reported between combustion 
products (particularly wood smoke) and cancer of the nasopharynx.
    NAS's positive finding of ``limited/suggestive evidence of an 
association'' between exposure to combustion products and cancers of 
the nasal cavity and nasopharynx was based on 4 epidemiological case-
control studies. These studies involved patients with nasal cavity and 
nasopharynx cancer, who were exposed regularly to combustion products, 
by virtue of their occupation or in their daily lives, over many years. 
Relevant exposures included exposure to fumes from the burning of wood 
and other materials, use of fuels, and occupational exposures such as 
working as a motor vehicle driver. Although NAS found these studies 
showed inconsistent results, they concluded that positive associations 
were reported by studies conducted in China between combustion products 
(particularly wood smoke) and cancer of the nasopharnyx.
    NAS's positive finding of ``limited/suggestive evidence of an 
association'' between exposure to combustion products and cancers of 
the oral cavity and oropharynx was based on 9 epidemiological case-
control studies. These epidemiological studies were of oral cavity and 
oropharynx cancer patients who were exposed to ambient air pollution in 
the cities where they lived, or who were exposed over many years due to 
their occupation or to indoor pollution in their homes due to 
combustion products from wood, coal, kerosene or gas burning stoves or 
heaters. Occupational exposures included working as a motor vehicle 
driver or railroad employee. NAS concluded that results of several 
studies suggested an association between cancers of the oral cavity and 
oropharynx and exposure to combustion products.
    NAS's positive finding of ``limited/suggestive evidence of an 
association'' between exposure to combustion products and laryngeal 
cancer was based on one epidemiological cohort study of workers exposed 
to diesel exhaust, and 16 epidemiological case-control studies of 
patients with laryngeal cancer. These studies involved people who were 
exposed to combustion products due to their occupations as railway 
workers, motor

[[Page 50859]]

vehicle drivers, or as city commuters exposed to ambient air pollution. 
The studies also included people who used wood and other fuel burning 
stoves regularly. Several studies reported positive findings, including 
two studies regarding exposure to the emissions of fossil-fuel stoves 
and one study regarding exposure to wood-stove emissions. Several 
studies reported small increases in laryngeal-cancer risk for some 
exposures; however, overall, the results were inconsistent. NAS 
concluded that the epidemiologic literature overall provided limited/
suggestive evidence of an association between exposure to combustion 
products and laryngeal cancer.
    NAS found ``limited/suggestive evidence of an association'' between 
exposure to combustion products and bladder cancer. Studies that 
assessed the relationship between exposure to combustion products and 
bladder cancer have not been consistently positive, and no studies 
assessed measurements of exposure. One pooled analysis of occupational 
exposures found questionably increased risks in exhaust-related 
occupations, and the risk was increased with higher exposures to 
polycyclic aromatic hydrocarbons (PAHs) and benzopyrene, which are 
combustion products. A slightly increased risk was observed for diesel 
exhaust. In a related study, similar findings were noted with some 
exposures to exhausts and PAHs. A more detailed assessment of PAH 
exposures based on expert review of work-history information found 
apparently stable associations with average and cumulative PAH 
exposures and total duration of PAH exposures. Taken together, the 
results constituted limited or suggestive evidence of an association 
between combustion products and bladder cancer, but the lack of 
exposure measurements and the heterogeneity of results precludes 
classifying the association as sufficient.
    NAS's positive finding of ``limited/suggestive evidence of an 
association'' between exposure to combustion products during pregnancy 
and low birthweight or intrauterine growth retardation was based on 8 
epidemiological studies of pregnant women. These women were exposed to 
ambient air pollution ``smog'' in heavily polluted cities in the Czech 
Republic where coal was burned, and in urban cities located in South 
Korea, China, Canada, and the United States.
    Two studies found evidence of a relationship between low 
birthweight or intrauterine growth retardation and combustion-product 
exposure. Their analyses controlled for several known risk factors, 
including maternal smoking. Several other studies reviewed by NAS 
provided supportive evidence of a relationship, but most were unable to 
adjust for maternal smoking.
    NAS's positive finding of ``limited/suggestive evidence of an 
association'' between exposure to combustion products during pregnancy 
and preterm birth was based on four epidemiological studies. The 
studies that found evidence of a relationship between preterm birth and 
combustion-product exposure were based primarily on maternal residence 
during pregnancy. Most of these studies controlled for several known 
risk factors for preterm birth (such as maternal age, race, education, 
and access to prenatal care), but none of the studies could completely 
control for maternal smoking, which is an important risk factor for 
preterm birth.
    NAS's positive finding of ``limited/suggestive evidence of an 
association'' between exposure to combustion products and asthma was 
based primarily on two studies, which evaluated an association between 
asthma and exposure to combustion products in ambient air pollution. 
NAS also relied on a study of veterans of the 1991 Gulf War that found 
an association between oil-well fire smoke and asthma, and a study 
associating ``biomass combustion'' and asthma among people over 60 
years old living in India.
    The epidemiological studies found that new cases of asthma were 
associated with combustion-product exposure in air pollutants. A study 
of Gulf War veterans using an objective exposure-measurement method, 
found an association between oil-well fire smoke and asthma in Gulf War 
veterans, but could not distinguish between new cases arising after the 
war and exacerbation of pre-existing conditions. Although the other key 
Gulf War study found no relationship between exposure and asthma, its 
definition of asthma was inadequate. Other studies of biomass-fuel 
combustion and outdoor air pollution supported a relationship between 
combustion exposure and asthma.
    The Secretary has determined that, although there is limited/
suggestive evidence of an association between exposure to combustion 
products and cancers of the nasal cavity and nasopharynx; cancers of 
the oral cavity and oropharynx; laryngeal cancer; bladder cancer; low 
birthweight/intrauterine growth retardation (with exposure during 
pregnancy); preterm birth (with exposure during pregnancy); and 
incident asthma, VA does not consider this exposure to be ``associated 
with'' the 1991 Gulf War. Please see section IV for further detail.
3. Inadequate/Insufficient Evidence
    NAS found inadequate/insufficient evidence between exposure to 
combustion products and esophageal cancer; stomach cancer; colon 
cancer; rectal cancer; hepatic cancer; pancreatic cancer; melanoma; 
female breast cancer; male breast cancer; female genital cancers 
(cervical, endometrial, uterine, and ovarian cancers); prostatic 
cancer; testicular cancer; nervous system cancers; ocular melanoma; 
kidney cancer; non-Hodgkin's lymphoma; Hodgkin's disease; multiple 
myeloma, leukemia; myelodysplastic syndromes; preterm births (based on 
exposure during a specific time period during pregnancy, such as the 
first trimester); low birth weight and intrauterine growth retardation 
(based on exposure before gestation or during a specific period during 
pregnancy, such as the first trimester); specific birth defects, 
including cardiac effects (with maternal or paternal exposure before 
conception or maternal exposure during early pregnancy); all childhood 
cancers identified, including acute lymphocytic leukemia, leukemia, 
neuroblastoma, and brain cancer; neurobehavioral effects; post-
traumatic stress disorder; nervous system subgroupings (or individual 
nervous system diseases); Multiple Chemical Sensitivity symptoms; 
chronic bronchitis (less than 1 year of exposure); emphysema; chronic 
obstructive pulmonary disease; ischemic heart disease or myocardial 
infarction (less than 2 years of exposure); dermatitis-irritant and 
allergic; and sarcoidosis.
    NAS reviewed five studies of combustion products and esophageal 
cancer, and concluded that no consistent association was observed in 
those studies.
    NAS reviewed six studies of combustion products and stomach cancer. 
Two of the studies reported an increased risk for stomach cancer, but 
the method used to assess exposure was limited and there were no 
adjustments for confounders.
    Studies of exposure to combustion products and colon cancer 
reported positive associations for exposure to some combustion 
products, but not to others. Further, a number of the positive findings 
were limited, due to their large confidence intervals. NAS found that 
the evidence of an association was inadequate because of the small 
number of studies available.
    With regard to rectal cancer, NAS found the studies' results were 
inconsistent, and the number of studies was small. NAS also noted that 
any

[[Page 50860]]

positive studies failed to include at least one high-quality study 
supported by an adequate exposure assessment.
    NAS noted only one relevant study that evaluated exposure to 
combustion products and hepatic cancer. Although associations were 
noted for some occupations, there were few cases with relevant 
exposure, and the study did not consider all pertinent risk factors.
    The four reviewed studies of combustion-product exposure and 
pancreatic cancer generally did not provide evidence of an association. 
One study found an association between exposure to coal combustion 
products and increased risk of pancreatic cancer, but it did not find a 
link between nine other types of combustion products and pancreatic 
cancer.
    Studies regarding melanoma addressed exposure to combustion 
products but their reliability is limited because they failed to adjust 
for exposure to sunlight, a major risk factor for melanoma. Overall, 
the studies did not report significant findings of association for most 
types of exposure. Two studies found isolated effects of specific 
exposures (propane exhaust and being a traffic administrator, 
respectively) that were not among the major exposures considered by 
NAS.
    NAS reviewed three studies concerning nonmelanoma skin cancer and 
combustion products. The studies generally did not report statistically 
significant findings of an association. NAS found that for the more 
common type of nonmelanoma skin cancer (basal cell carcinoma), the 
findings were largely negative. Two of the studies stated findings 
regarding squamous cell carcinoma, with one finding a statistically 
significant association for one type of exposure (diesel fumes), but 
not others, and one study finding no association.
    The two studies involving female breast cancer and exposure to 
combustion products essentially had negative results.
    Of the two reviewed studies regarding exposure to combustion 
products and male breast cancer, one did not find an association 
between PAH exposure and male breast cancer, and the other, although 
reporting a positive association, was limited by its method of exposure 
assessment.
    NAS reviewed three studies regarding exposure to fuels or 
combustion products and cervical, endometrial, uterine, or ovarian 
cancer, and found that they provided inadequate support for an 
association.
    NAS reviewed four prostate cancer studies that measured the 
relationship between occupations having potential for exposure to 
combustion products or PAHs or having more rigorously derived estimates 
of exposure to such agents and prostatic cancer. Although the studies 
reported several positive associations, NAS noted that the results were 
not consistently positive. For example, one study showed results 
contrary to a dose-response relationship, while another study showed an 
increased risk in firefighters and railroad workers but not in other 
transportation or trucking workers.
    Testicular cancer studies did not provide enough relevant data to 
draw any sort of conclusion about exposure to fuels or combustion 
products and testicular cancer.
    Data on combustion products and brain cancer (nervous system 
cancers) were too sparse to determine whether an association exists.
    Three studies of ocular melanoma reported increased, but imprecise, 
risks of ocular melanoma in occupations related to transportation. The 
reliability of these studies is limited by their small size, lack of 
statistical significance, and lack of adequate exposure assessment.
    Although some studies of exposure to combustion products and kidney 
cancer suggested a possible association based on job title, NAS found 
that the results were not consistently positive, with some studies 
showing no increased risk. Further, the results of some studies showing 
positive associations were limited by considerations of statistical 
significance and other factors.
    Studies on non-Hodgkin's lymphoma (NHL) had no firmly positive 
findings. In the study with the most objective exposure assessment, 
there was no indication of an association with any of the fuels or 
their combustion products.
    The studies regarding Hodgkin's disease (HD) were limited by their 
small numbers of cases and the nonspecificity of their exposure 
assessments. Further, the three primary studies reviewed by NAS showed 
findings of no association.
    NAS reviewed ten studies concerning multiple myeloma and exposure 
to combustion products. Three of the studies the NAS found to be among 
the most sizable or significant reported only marginally increased 
risks and are just barely suggestive of an association. Other studies 
showed no association, and yet other studies are limited due to 
imprecise estimates of increased multiple-myeloma risk in association 
with exhaust exposure and concerns regarding exposure assessments. NAS 
concluded that the literature overall provided insufficient evidence of 
an association.
    NAS reviewed six studies of leukemia and exposure to combustion 
products. Four of the studies showed no findings of a statistically 
significant increased risk. In the other two studies, the apparent 
associations were related to separate types of leukemia, and the 
authors of the studies noted that any increase in leukemia risk was 
difficult to attribute specifically to exhaust because of concurrent 
exposure to fuels and benzene. The exposure assessments in all the 
studies were based on information from sources of questionable 
reliability (personal interviews or medical records) or had a low 
degree of specificity for combustion products.
    NAS reviewed two studies regarding myelodysplastic syndromes and 
exposure to combustion products. One study found no significant 
evidence of an association. The other study found stable evidence of an 
association for the not particularly substance-specific occupation of 
machine operator. Further, the reliability of that study is limited 
because the analyses by researchers were rudimentary and failed to 
adjust for possible confounders when the information was available.
    As noted above in section III.A.2, NAS found limited/suggestive 
evidence of an association between exposure to combustion products 
during pregnancy and preterm birth. NAS similarly found limited/
suggestive evidence of an association between exposure to combustion 
products during pregnancy and low birth weight or intrauterine growth 
retardation. However, NAS also found that there was inadequate/
insufficient evidence of an association between combustion products 
exposure at any specific point during pregnancy (such as the first 
trimester) and these reproductive effects. Although several of the 
studies NAS reviewed reported results for exposure at different stages 
of pregnancy, there were no consistent findings as to whether the risks 
were greater with exposure early or late in pregnancy. Additionally, 
none of the studies completely controlled for the significant risk 
factor of smoking during pregnancy.
    One study of an association between maternal exposure to air 
pollutants and the risk of birth defects reported relationships between 
certain cardiac defects and increasing exposure to CO and O3. NAS 
discussed two studies that examined the association between paternal 
employment as a firefighter and the risk of cardiac birth defects. One 
of the studies found no evidence of an association, while the other 
found some evidence that certain cardiac defects were associated with 
paternal employment as a firefighter. Both studies had limitations due 
to size,

[[Page 50861]]

potential confounding and/or inadequate information about duration of 
paternal firefighting. In a study of maternal or paternal exposures 
among residents of 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.
    NAS discussed eleven studies of the association between combustion-
products exposure and childhood cancers, including acute lymphocytic 
leukemia, leukemia, neuroblastoma, and brain cancer. All of the studies 
were limited by their inability to validate employment history and by 
the lack of details on specific assessments of exposure to combustion 
products. The exposure groups were broad and included many diverse 
occupations where exposure to other chemicals was noted in addition to 
combustion products. Six of the studies found no association between 
combustion products exposure and the studied childhood cancers. One 
study reported general findings of associations for a variety of 
childhood cancers, while the remaining four studies contained mixed 
findings, reporting positive associations for certain types of cancers.
    All of the studies on neurobehavioral effects and combustion-
product exposure suffered from significant methodological limitations. 
Several Gulf War studies reported positive relationships between self-
reported exposure and self-reported neuropsychologic, cognitive, or 
mood symptoms or multiple unexplained symptoms, but the lack of 
objective measurement of exposure limits the reliability of those 
findings. Among two non-veteran studies reporting positive findings for 
certain neurobehavioral effects, one study did not have a control 
group, and the other had serious limitations, especially in subject 
selection.
    NAS identified no studies showing an association between 
combustion-products exposure and post-traumatic stress disorder (PTSD). 
Although several studies addressed the prevalence of PTSD among 
firefighters, the result is most likely attributable to the hazardous 
nature of the job rather than exposure to combustion products. Only a 
few Gulf War studies have examined whether self-reported combustion-
product exposure was related to PTSD as an outcome measure, and none 
has found such a relationship. None of the studies with objectively 
measured oil-well fire smoke examined PTSD as an outcome measure.
    Regarding nervous system disease subgroupings (or individual 
nervous system diseases), NAS excluded studies involving only overbroad 
and nonspecific health outcomes and focused on individual neurologic 
diseases or subgroupings of nervous-system diseases. Only two 
identified studies examined nervous-system subgroupings in relation to 
combustion-products exposure. One study found exposure-response 
relationships with nervous-system subgroupings in a hospital discharge 
survey. The limitation of this study was assignment of exposure 
(residence only) and potential for exposure misclassification. The 
other study did not find a relationship between combustion product 
exposure and multiple sclerosis. No other studies of nervous system 
subgroups or the individual diseases met NAS's criteria for inclusion.
    Although NAS reviewed several studies of Multiple Chemical 
Sensitivity (MCS) in Gulf War veteran or civilian samples, those 
studies provided relatively little evidence that MCS was associated 
with combustion-products exposure in service. Several studies involved 
questionnaires on which veterans or civilians self-reported that 
exposure to certain combustion products (e.g., tobacco smoke, car 
exhaust) are among the factors that can trigger their symptomatology. 
However, NAS noted that most of the studies did inquire as to the first 
onset of symptoms. Further, the studies generally were limited by 
methodologic concerns, including self-reported exposures and symptoms 
and the possibility of recall bias.
    Although the studies reviewed by NAS indicated a probable 
relationship between long-term (over 1 year) exposure to combustion 
products and chronic bronchitis, a key unresolved issue was whether 
shorter-term exposures (less than 1 year) can cause the condition. NAS 
found inadequate published data that addressed the effect of shorter 
term combustion-product exposures (less than 1 year) on the risk of 
developing chronic bronchitis. Even if it could be shown that long-term 
exposure to combustion products caused chronic bronchitis, it might be 
expected to cease after exposure without long-term health consequences. 
NAS found inadequate published data to evaluate the natural history of 
chronic bronchitis after cessation of exposure to combustion products.
    A study found that mortality due to emphysema was not considerably 
increased among workers exposed to diesel exhaust. This result was 
found after adjustments for the effects of smoking were made. Likewise, 
a study of veterans exposed to oil-well fires also did not find a 
relationship with emphysema. Other studies that included emphysema in 
the analysis were methodologically inadequate.
    NAS did not identify any high-quality studies that evaluated the 
effect of exposure to combustion products on the risk of chronic 
obstructive pulmonary disease (COPD), as defined by objective evidence 
of irreversible airflow obstruction with spirometry. Several studies of 
biomass-smoke exposure used measures of airflow obstruction but had 
methodologic limitations that precluded clear conclusions about the 
connection between combustion exposure and COPD.
    There was relatively consistent epidemiologic evidence of the 
relation between ischemic heart disease (including myocardial 
infarction) and long-term exposure to fossil-fuel combustion products, 
including motor-vehicle exhaust and combustion-derived fine particulate 
matter. However, the increased risk was small in absolute terms, and 
there was no adequate epidemiologic evidence to support the role of 
relatively short exposures (similar to that experienced in the Gulf 
War), followed by an exposure-free period, and then development of 
ischemic heart disease events. Accordingly, NAS found inadequate/
insufficient evidence to determine whether an association exists 
between short-term exposure (less than 2 years) to combustion products 
and the development of ischemic heart disease after an exposure-free 
period of months or years.
    Rashes were frequently reported by Gulf War veterans, but only one 
study of Gulf War veterans searched for relationships between 
dermatitis and self-reported exposure during the Gulf War. No exposure 
to combustion products or any other self-reported exposure was related 
to dermatitis, defined as rashes, eczema, or skin allergies.
    NAS identified three epidemiologic studies on the relationship 
between occupational or residential exposure to fires and sarcoidosis, 
all of which had significant methodologic limitations. One study had 
numerous limitations, such as inadequate description of how the cases 
without biopsy confirmation were diagnosed and the lack of control for 
employment history (besides farming), recall bias, and lack of 
measurement of pollutant concentrations. The authors noted that 
sarcoidosis could be associated with a component of wood-burning or 
wood-

[[Page 50862]]

handling, namely contact with smoke, ash, wood particles, or wood 
molds. Another study was limited by the lack of specific exposure 
assessment and of analysis of duration or frequency of exposure to 
combustion products. There was no control for potential confounders, 
such as race or familiar aggregation of sarcoidosis. In addition, there 
was no way to determine the role of combustion products or exposure to 
other toxicants, allergens, or infectious agents. The third study was 
limited by the small sample, the low statistical power, the lack of a 
risk estimate for firefighters versus police officers, the lack of 
exposure assessment for combustion products, and the lack of assessment 
of coexposures to other chemicals in the workplace.
    Based on the information and analysis in the NAS report, the 
Secretary has determined that there is insufficient credible evidence 
to conclude that there is a positive association between exposure to 
combustion products and esophageal cancer; stomach cancer; colon 
cancer; rectal cancer; hepatic cancer; pancreatic cancer; melanoma; 
nonmelanoma skin cancer; female breast cancer; male breast cancer; 
female genital cancers (cervical, endometrial, uterine, and ovarian 
cancers); prostatic cancer; testicular cancer; nervous system cancers; 
ocular melanoma; kidney cancer; non-Hodgkin's lymphoma; Hodgkin's 
disease; multiple myeloma, leukemia; myelodysplastic syndromes; preterm 
births (based on exposure during any specific time period during 
pregnancy, such as the first trimester); low birth weight and 
intrauterine growth retardation (based on exposure before gestation or 
during any specific period during pregnancy, such as the first 
trimester); specific birth defects, including cardiac effects (with 
maternal or paternal exposure before conception or maternal exposure 
during early pregnancy; all childhood cancers identified, including 
acute lymphocytic leukemia, leukemia, neuroblastoma, and brain cancer; 
neurobehavioral effects; post-traumatic stress disorder; nervous system 
disease subgroupings (or individual nervous system diseases); MCS 
symptoms; chronic bronchitis (less than 1 year of exposure); emphysema; 
chronic obstructive pulmonary disease; ischemic heart disease or 
myocardial infarction (less than 2 years of exposure); dermatitis-
irritant and allergic; and sarcoidosis. Further, as explained in 
section IV of this notice, VA does not consider the combustion-products 
exposures underlying the NAS findings to be exposures ``associated 
with'' the 1991 Gulf War. Therefore, a presumption of service 
connection is not warranted for any such illness based upon exposure to 
combustion products during service in the Gulf War.

B. Hydrazines

1. Limited/Suggestive Evidence of an Association
    NAS found limited/suggestive evidence of an association between 
exposure to hydrazines (monomethylhydrazine ``MMH,'' and unsymmetrical 
(1,1-)dimethylhydrazine ``UDMH'') used as rocket propellants, and lung 
cancer. This conclusion was based primarily on one high-quality study, 
as discussed below.
    An occupational study of a U.S. cohort of aerospace workers engaged 
in testing rockets using hydrazine fuel demonstrated an association 
between hydrazine exposure and risk of lung cancer. Several sources of 
potential confounding, including sex and radiation exposure, were 
controlled by study design. Other potentially confounding variables 
were controlled in multivariate analysis, including age, pay type, and 
time since hire or transfer. Although the smoking status of most 
workers was unknown, there was indirect evidence that smoking did not 
confound the results.
    Two other studies of lung cancer were limited by small sample size 
and inadequate study power. In addition, another study was limited by 
its failure to control for coexposure to other carcinogenic substances, 
including asbestos and PAHs. The lack of internal control subjects and 
the lack of information on smoking constitute major limitations for 
both studies. Consequently, there was inadequate evidence to evaluate 
the consistency of the association between hydrazine and lung cancer 
beyond the study of the U.S. cohort.
    NAS stated in its report that U.S. military personnel could have 
been exposed to UMDH during Operation Desert Storm if UMDH was used as 
a rocket fuel in Scud missiles launched by Iraq and the U.S. military 
personnel were in the vicinity of the Scud missiles when they 
disintegrated. However, NAS stated that hydrazines were apparently not 
used in Scud missiles during the 1991 Gulf War even though Iraq had 
apparently experimented with UDMH as a rocket fuel. NAS further stated 
that it was not aware of any other potential use of hydrazines that 
could have resulted in exposure of U.S. service personnel.
    Based on information and analysis in the NAS report and from DoD, 
VA does not consider exposure to hydrazines to be exposures 
``associated with'' the 1991 Gulf War. Please see section IV for 
further detail. Therefore, a presumption of service connection is not 
warranted for lung cancer based upon exposure to hydrazine during 
service in the 1991 Gulf War.
2. Inadequate/Insufficient Evidence
    NAS found inadequate/insufficient evidence between hydrazines and 
hematopoietic and lymphopoietic cancers; digestive tract cancers; 
pancreatic cancer; bladder cancer; kidney cancer; emphysema; ischemic 
heart disease or myocardial infarction; and hepatic disease.
    NAS noted that relatively few studies existed concerning the health 
effects of hydrazine exposure, and that lung cancer was the only health 
outcome represented in all three cohort studies reviewed by the 
committee. NAS further noted that individual findings in those studies 
also reported somewhat increased mortality from cancer at sites other 
than the lung (hematopoietic and lymphopoietic, bladder and kidney, 
digestive tract, and pancreas) and from two noncancer conditions 
(emphysema and ischemic heart disease). NAS concluded, however, that 
the few available studies do not provide adequate or consistent 
evidence of an association between exposure to hydrazines and any of 
those other health outcomes.
    Based on the information and analysis in the NAS report, the 
Secretary has determined that there is insufficient credible evidence 
to conclude that there is a positive association between exposure to 
hydrazines and hematopoietic and lymphopoietic cancers; digestive tract 
cancers; pancreatic cancer; bladder cancer; kidney cancer; emphysema; 
ischemic heart disease or myocardial infarction; and hepatic disease. 
Further, as explained in section IV of this notice, VA does not 
consider exposure to hydrazines to be exposures ``associated with'' the 
1991 Gulf War. Therefore, a presumption of service connection is not 
warranted for any such illness based upon exposure to hydrazine during 
service in the 1991 Gulf War.

C. Fuels--Inadequate/Insufficient Evidence

    NAS found inadequate/insufficient evidence of an association 
between exposure to fuels and cancers of the oral cavity and 
oropharynx; cancers of the nasal cavity and nasopharynx; esophageal 
cancer; stomach cancer; colon cancer; rectal cancer; hepatic cancer; 
pancreatic cancer; laryngeal cancer; lung cancer; melanoma; nonmelanoma 
skin cancer; female breast

[[Page 50863]]

cancer; male breast cancer; female genital cancers (cervical, 
endometrial, uterine, and ovarian cancers); prostatic cancer; 
testicular cancer; nervous system cancers; kidney cancer; bladder 
cancer; Hodgkin's disease; non-Hodgkin's lymphoma; multiple myeloma; 
myelodysplastic syndromes; adverse reproductive or developmental 
outcomes (including infertility, spontaneous abortion, childhood 
leukemia, CNS tumors, neuroblastoma, and Prader-Willi syndrome); 
peripheral neuropathy; neurobehavioral effects; MCS symptoms; 
nonmalignant respiratory disease; chronic bronchitis; asthma; 
emphysema; dermatitis-irritant and allergic; and sarcoidosis.
    NAS reviewed five studies regarding cancer of the oral cavity and 
oropharynx and fuels. NAS found that the three occupational cohort 
studies it reviewed each had limited statistical power and were 
therefore uninformative. NAS further concluded that the two case-
control studies it reviewed failed to report any consistent 
relationship between fuel exposure and cancers of the oral cavity and 
oropharynx.
    NAS found little information available on exposure to fuels and 
cancers of the nasal cavity and nasopharynx, and that the two studies 
it reviewed failed to provide convincingly positive findings.
    NAS found that studies of an association between fuel exposure and 
esophageal cancer were few and results were inconsistent and inadequate 
to support an association. Some of the studies were unreliable because 
they analyzed esophageal cancer and stomach cancers together, and NAS 
therefore could not determine which specific cancer type may have been 
associated with fuel exposure. Other studies showed no evidence of 
association.
    NAS also found that studies of an association between fuel exposure 
and stomach cancer were inconsistent and inadequate to support an 
association. As noted above, some of the studies were unreliable 
because they analyzed esophageal cancer and stomach cancers together in 
relation to fuel exposure and NAS could not determine which specific 
cancer type may have been associated with fuel exposure. Other studies 
showed no evidence of association.
    NAS found that the studies concerning fuel exposure and colon 
cancer provided no consistent evidence of an association. Although some 
studies showed increased risk of colon cancer, the increases were 
modest and the confidence intervals in several instances included the 
null. Three studies analyzed colon cancer and rectal cancer together 
and, therefore, NAS could not determine whether exposure to fuels may 
have been associated with a specific type of cancer.
    NAS found that the studies reporting positive associations between 
fuels and rectal cancer were not consistent and the number of studies 
was small. Furthermore, the positive studies failed to include at least 
one high-quality study supported by an adequate exposure assessment. 
Some studies found no evidence of association between fuel exposure and 
rectal cancer.
    NAS noted only one relevant study that evaluated exposure to fuels 
and hepatic cancer in which there were few cases with relevant 
exposure, and the study did not consider all pertinent risk factors.
    NAS found only two relevant studies on the risk of pancreatic 
cancer posed by fuel exposure. One study found no association. The 
other study reported an association, but the results were imprecise, 
due in part to a large confidence interval that included the null.
    NAS found that the results regarding exposure to fuels and 
laryngeal cancer were inconsistent. Two studies reviewed by NAS 
reported a modest increase in the risk of laryngeal cancer associated 
with exposure to fuels, but the reliability of those findings is 
limited because the exposures in both studies were self-reported. 
Another study reported an increased, but imprecise, risk of laryngeal 
cancer in vehicle mechanics, but found no increase in garage and 
gasoline-station workers.
    NAS found the results of studies of fuel exposure and lung cancer 
risk were inconsistent. One study reported an association between 
kerosene and crude-oil exposure and squamous-cell lung cancer, between 
diesel-fuel exposure and nonadenocarcinoma, and between heating-oil 
exposure and oat-cell lung cancer. Two studies did not find an 
association in workers most likely to have been exposed to fuels.
    The studies examined by NAS addressing melanoma and exposure to 
fuels were not adjusted for sun exposure, a major risk factor for 
melanoma, and the workers--particularly the exploration, drilling, and 
pipeline workers--may have received considerable sun exposure while 
performing their jobs. But the one case-control study with fairly 
reliable exposure analysis did not support an association in workers 
likely to have been exposed to fuels.
    Of the available epidemiologic studies regarding nonmelanoma skin 
cancer that met NAS's criteria, one study reported one borderline 
association between fuel exposure and squamous-cell carcinoma. The 
other two reports reviewed by NAS had methodologic limitations and did 
not provide reliable evidence of an association. For the more common 
type of nonmelanoma skin cancer (basal cell carcinoma), the findings 
were largely negative.
    NAS reviewed three studies concerning fuel exposure and female 
breast cancer. One study found no increased risk of breast cancer, 
while the other two found only an insignificant increase in risk.
    NAS found no studies assessing the possible relationship of male 
breast cancer to fuel exposure alone. NAS reviewed one study that 
reported a positive finding regarding combined exposure to fuels and 
combustion products and male breast cancer. NAS found, however, that 
the method used to assess exposure in that study was limited.
    NAS reviewed three studies concerning fuel exposure and female 
genital cancers. The studies failed to provide any significant evidence 
of an association between exposure to fuels and cervical, endometrial, 
uterine, or ovarian cancer.
    NAS reviewed several studies regarding an association between fuel 
exposure and prostatic cancer. Only one of those studies reported a 
positive association between a fuel-related exposure and prostatic 
cancer. That study found an association between exposure to diesel fuel 
and prostate cancer, but did not find significant evidence of an 
association for other types of fuel exposure. The other reports 
reviewed by NAS were negative for any association.
    Only one study addressed the association between fuel exposure and 
testicular cancer, and it found no evidence of an association. NAS 
concluded that there was not enough relevant data to draw any sort of 
conclusion about exposure to fuels and testicular cancer.
    Several studies reported sporadic associations between fuel 
exposure and nervous system cancers (brain cancer), but the results 
were limited by several factors, including wide confidence intervals 
that include the null. In some studies, the increased risk was found 
only among workers likely to have lesser fuel exposure, while no 
increased risk was seen among workers likely to have greater fuel 
exposure. None of the studies could be considered a high-quality study 
supported by an adequate

[[Page 50864]]

exposure assessment. Additionally, some studies found no evidence of 
association.
    No key study that was positive for an association between exposure 
to fuels and kidney cancer was identified. NAS found the uniformly 
negative results of a study of a comprehensive sample of renal cell 
carcinoma cases in the petroleum industry with excellent exposure 
assessment to be compelling.
    NAS reviewed several studies concerning fuel exposure and bladder 
cancer. Several of the studies found no evidence or no significant 
evidence of an association. Other studies provided evidence of a 
relationship between fuel exposure and bladder cancer, but the 
relationship was not consistently increased in any study with a 
detailed and specific exposure assessment. The positive findings in 
some studies were further limited by the methods used to estimate 
exposure and the difficulty in segregating fuel exposure from 
combustion-product exposure in some instances.
    Regarding Hodgkin's disease, the studies were limited by their 
small numbers of cases and the nonspecificity of their exposure 
assessments. Of the five studies reviewed by NAS, two found no evidence 
of an association between fuel exposure and Hodgkin's disease, one 
found an insignificant increase only among males. The other two studies 
showed evidence of an association, but were limited by wide confidence 
intervals and the lack of any relationship to a specific job or 
duration of employment.
    Studies on non-Hodgkin's lymphoma had no firmly positive findings. 
The most well conducted studies showed no evidence of association.
    NAS found no consistent relationship between exposure to fuels and 
multiple myeloma in the studies reviewed. Most studies reported no 
association.
    NAS reviewed two studies that showed evidence of an association 
between myelodysplastic syndrome and exposure to petroleum-related 
substances. However, a significantly larger study using similar methods 
and procedures failed to produce consistent results. The larger study 
reported only a modest increased risk, with confidence intervals 
including the null, and did not find any evidence of a dose-response 
relationship with duration or intensity of exposure.
    NAS determined that it was difficult overall to reach conclusions 
on the epidemiologic studies of adverse reproductive outcomes and 
exposure to fuels. The assessment of findings was 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. NAS found no adequate studies regarding the 
relationship between fuel exposure and female infertility. NAS found 
one study concerning fuel exposure and male fertility, and that study 
showed no effect on sperm measures among persons exposed to jet fuels. 
NAS found only one study on fuel exposure and spontaneous abortion. The 
study showed a significant increase in spontaneous abortion among women 
living in an area where water used for drinking, cooking, and bathing 
was contaminated by nearby oil fields, however, the finding was 
potentially limited by recall bias and methods of estimating exposure. 
NAS identified one study showing an increased risk of childhood 
leukemia in the offspring of men exposed to petroleum for 1,000 days or 
more before conception, and one study showing an increased risk of 
childhood leukemia based on maternal exposure to fuels during 
pregnancy. The latter study was potentially limited by recall bias, 
interviewer bias, control-selection procedures, and lack of validation 
for other risk factors. NAS noted that three other occupational studies 
showed no relationship between parental employment in a field involving 
fuel exposure and childhood leukemia. With respect to childhood cancers 
of the central nervous system, NAS identified one study showing no 
increase in neuroblastoma based on maternal exposure to fuels during 
pregnancy, but moderate increases based on paternal exposures. The 
study authors were unable to distinguish between paternal exposures 
occurring before or after conception. Another study showed an increased 
risk of neuroblastoma based on maternal or paternal exposures, although 
the study authors noted several limitations on the interpretation of 
the data, including bias, chance, and self-reporting of exposure 
information. NAS noted that two studies showed a possible association 
between parental exposure to hydrocarbons and the occurrence of Prader-
Willi Syndrome in offspring, although neither study collected 
information on potential confounders. A third study found no 
association between exposure to hydrocarbons and Prader-Willi Syndrome 
in offspring. In view of the minimal and indeterminate data, NAS 
concluded that there was inadequate/insufficient evidence of an 
association between parental fuel exposure and adverse reproductive or 
developmental outcomes.
    Regarding neuropathy, NAS reviewed two studies, in which certain 
neurological symptoms were more prevalent among subjects with higher 
exposures to jet fuels, while other neurological symptoms were either 
not increased or were more prevalent among controls. NAS concluded 
that, although certain symptomatic differences were apparently related 
to exposure, there were no objective measures to support a relationship 
between jet-fuel exposure and neuropathy. The limitations of the 
studies included small samples and the lack of internal nonexposed 
groups of controls.
    Regarding neurobehavioral effects, NAS found that several studies 
of Gulf War veterans found a relationship between the veterans' self-
reported fuel exposure and their self-reported neuropsychologic, 
cognitive, or non-specific symptoms, but that these studies provided 
weak evidence of any relationship, due to recall bias. NAS also 
discussed a study of increased neurologic and cognitive abnormalities 
among persons who engaged in ``petrol-sniffing,'' but found those 
results inconclusive because the effects were most likely due to 
exposure to lead rather than the fuels themselves.
    NAS found that studies of MCS in Gulf War veteran or civilian 
samples generally provided relatively little evidence that MCS was 
associated with fuel exposure in service. Several studies involved 
questionnaires on which veterans or civilians self-reported that 
exposure to fuels are among the factors that can trigger their 
symptomatology. The studies generally were limited by methodologic 
concerns, including self-reported exposures and symptoms and the 
possibility of recall bias. Further, NAS noted that most of the studies 
did not address the factors relating to the first onset of symptoms as 
distinguished from subsequent recurrence of symptoms. The only study 
addressing first onset was an occupational study that incorporated 
objective exposure measurement and found a relationship between 
symptoms of MCS and fuel exposure. However, because the study was 
limited by the small sample and lack of a matched control group of 
workers, NAS found that it did not meet the criteria for a primary 
study that could support an association.
    Regarding respiratory diseases, the studies generally did not 
report specific respiratory disease outcomes and exposure assessment, 
so it was difficult to reach a conclusion as to a relationship between 
respiratory disease outcomes and exposure to fuels. However, NAS noted 
that most of the studies it reviewed showed

[[Page 50865]]

standardized mortality ratios of 1.0 or less in study populations, 
showing no increased risk of death due to nonmalignant respiratory 
disease, asthma, chronic bronchitis, or emphysema in populations 
exposed to fuels.
    Regarding irritant contact dermatitis, many fuels (for example, 
gasoline and kerosene) were generally acknowledged skin irritants, as 
indicated by the studies reviewed by NAS. Irritant contact dermatitis 
was evident soon after exposure but usually disappeared soon after 
removal of the irritant. There are few epidemiologic studies, however, 
of exposure to fuels and irritant and allergic contact dermatitis. 
Accordingly, NAS concluded that there was inadequate/insufficient 
evidence of an association between fuel exposure and chronic irritant 
and allergic contact dermatitis after cessation of exposure.