United States
Environmental Protection
Agency
Office of Health and
Environmental Assessment
Washington DC 2O46O
EPA/600/6-87/001
April 1987
Research and Development
vvEPA
Evaluation of the
Carcinogenicity of
Unleaded Gasoline
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EPA/600/6-87/001
April 1987
EVALUATION OF THE CARCINOGENICITY
OF
UNLEADED GASOLINE
Carcinogen Assessment Group
Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, D.C.
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DISCLAIMER
This document has been reviewed in accordance with U.S. Environmental
Protection Agency policy and approved for publication. Mention of trade names
or commercial products does not constitute endorsement or recommendation for
use.
ii
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CONTENTS
Tables . . viii
Preface xi
Abstract xii
Authors, Contributors, and Reviewers • xiii
1. SUMMARY AND CONCLUSIONS 1-1
1.1. SUMMARY. , 1-1
V
1.1.1. Qualitative 1-1
1.1.1.1. Animal Studies . . 1-1
1.1.1.2. Epidemiologic Studies 1-2
; 1.1.2. Quantitative 1-3
1.2. CONCLUSIONS 1-4
2. INTRODUCTION 2-1
3. ANIMAL STUDIES 3-1
3.1. LIFETIME INHALATION BIOASSAY IN RATS AND MICE (INTERNATIONAL
RESEARCH AND DEVELOPMENT CORPORATION, 1983) 3-1
3.2. 90-DAY INHALATION EXPOSURE STUDY WITH GASOLINE VAPOR IN RATS
AND MONKEYS (MacFARLAND, 1983) 3-16
3.3. RENAL TOXICITY OF GASOLINE AND RELATED PETROLEUM NAPHTHA IN
MALE RATS (HALDER ET AL., 1984) 3-18
3.4. TOXICITY OF ORGANIC CHEMICALS PRESENT IN UNLEADED GASOLINE . 3-25
3.4.1. 13-Week Inhalation Toxicity Study of a 0° to 145°F
Gasoline Distillate Fraction in Rats (IIT Research
Institute, 1985a) 3-25
3.4.2. 13-Week Inhalation Toxicity Study of C4/C50 Hydro-
carbon Blends in Rats (IIT Research Institute,
1985b) 3-25
3.4.3. Renal Toxicity of Whole Unleaded Gasoline, Fractions
of Unleaded Gasoline, Various Naphthas, and Some
Individual Components, in Male Rats (Haider et al.,
1984) 3-26
3.4.4. 4-Week Oral Nephrotoxicity Screening Study in Male
F344 Rats (Tegeris Laboratories, 1985) .3-30
3.5. RENAL EFFECTS OF DECALIN IN SEVERAL LABORATORY MAMMALIAN
SPECIES (ALDEN ET AL., 1983) 3-30
3.6. TOXICITY OF SYNTHETIC FUELS AND MIXED DISTILLATES IN LABORA-
TORY ANIMALS (MacNAUGHTON AND UDDIN, 1983) 3-32
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CONTENTS (continued)
3.6.1. Studies with RJ-5 Synthetic Fuel . 3-32
3.6.2. Studies with JP-10 Synthetic Fuel. ......... 3-34
3.6.3. Studies with JP-4 Mixed Distillate . ........ 3-35
3.6.4. Studies with JP-5 . 3-36
3.7. INFLUENCE OF BENZENE ON THE RENAL CARCINOGENIC EFFECTS OF
UNLEADED GASOLINE VAPOR IN MALE RATS 3-37
3.8. CONCLUSIONS OF THE UAREP REPORT (1983) ON THE TOXICOLOGICAL
INTERPRETATION OF HYDROCARBON-INDUCED KIDNEY LESIONS .... 3-38
3.8.1. Assessment of the API Chronic Inhalation Study with
Unleaded Gasoline Vapor in Rats and Mice ...... 3-38
3.8.2. Interpretation of the Toxicological Carcinogenic
Findings in the Carcinogenicity Study with Unleaded
Gasoline by UAREP 3-39
3.8.3. Review of Human Kidney Lesions ........... 3-41
3.8.4. Species and Sex Comparison of the Kidney ...... 3-42
3.8.5. Rodent Kidneys and Other Hydrocarbons. ....... 3-44
3.8.6. Old-Rat Nephropathy 3-45
3.8.7. Comparative Nephrotoxicity and Nephrocarcinogenicity 3-46
3.8.8. Significance to Humans of the Chronic Inhalation
Study with Unleaded Gasoline Vapor in Rats and Mice. 3-47
3.9. RESEARCH IN PROGRESS OR PLANNED UNDER THE SPONSORSHIP OF THE
AMERICAN PETROLEUM INSTITUTE 3-47
3.10. SUMMARY OF ANIMAL STUDIES 3-48
4. EPIDEMIOLOGIC STUDIES 4-1
4.1. EPIDEMIOLOGIC STUDIES OF WORKERS IN THE GASOLINE SERVICE
INDUSTRY . 4-2
4.1.1. Stemhagen et al. (1983). .............. 4-2
4.1.2. Silverman et al. (1983) .......... 4-5
4.1.3. Mommsen et al. (1982; 1983a, b); Mommsen and Aagard
(1983a, b; 1984); Mommsen and Sell (1983) 4-11
4.1.4. Domiano et al. (1985). ..... 4-15
4.1.5. Lin and Kessler (1981) 4-17
4.1.6. Lin and Kessler (1979) .... ..... 4-20
4.1.7. Milham (1983) 4-20
4.2. EPIDEMIOLOGIC STUDIES OF WORKERS IN THE PETROLEUM INDUSTRY . 4-29
4,2.1. Mortality Studies of Workers in the Petroleum
Refining Industry. . 4-29
4.2.1.1. Tabershaw-Cooper Associates, Inc. (1974
Unpublished, 1975 Unpublished) . 4-29
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CONTENTS (continued)
4.2.1.2. Hanis (1977) 4-35
4.2.1.3. Hanis et al. (1979) 4-45
4.2.1.4. Theriault and Goulet (1979) 4-50
4.2.1.5. Thomas et al. (1980) 4-52
4.2.1.6. Wen et al. (1981, 1982, 1983, 1984a). . . 4-55
4.2.1.6.1. Wen et al. (1982). . 4-57
4.2.1.6.2. Wen et al. (1981) 4-60
4.2.1.6.3. Wen et al. (1983). 4-62
4.2.1.6.4. Wen et al. (1984a)-. ..... 4-65
4.2.1.7. Rushton and Alderson (1981a) 4-67
4.2.1.8. Schottenfeld et al. (1981) 4-70
4.2.1.9. Thomas et al. (1982a) 4-73
4.2.1.10. Reeve et al. (1982) ............ 4-76
4.2.1.11. Hanis et al. (1982) . 4-78
4.2.1.12. Rushton and Alderson (1983) ....... 4-81
4.2.1.13. Morgan and Wong (1983 Unpublished). . . . 4-84
4.2.1.14. Morgan and Wong (1984 Unpublished). . . . 4-91
4.2.1.15. Thomas et al. (1984). .......... 4-96
4.2.1.16. Wen et al. (1984b Summary) 4-102
4.2.1.17. Kaplan (1982 Unpublished, 1985 Un-
published). 4-107
4.2.1.18. McGraw et al. (1985) 4-110
4.2.1.19. Hanis et al. (1985a) 4-112
4.2.1.20. Hanis et al. (1985b) 4-116
4.2.1.21. Divine et al. (1985) 4-121
4.2.1.22. Barren and Divine (1985). ........ 4-123
4.2.1.23. Nelson (1985 Unpublished) 4-124
4,2.2. Case-Control Studies that Evaluated Employment in
the Petroleum Industry as a Risk Factor 4-129
4.2.2.1. Cole et al. (1972) 4-129
4.2.2.2. Howe et al. (1980) 4-132
4.2.2.3. Bladder Cancer Mortality Studies in
Louisiana 4-137
4.2.2.3.1. Gottlieb and Pickle (1981). . 4-137
4.2.2.3.2. Gottlieb and Carr (1981). . . 4-140
4.2.2.4. Najem et al. (1982) . 4-142
4.2.2.5.' Mclaughlin et al. (1984) 4-144
4.2.2.6. Mclaughlin et al. (1983). . 4-149
, 4.2.2.7. Pancreatic Cancer Mortality Studies in
Louisiana 4-151
4.2.2.7.1. Pickle and Gottlieb (1980). . 4-151
4.2.2.7.2. Gottlieb and Carr (1981). . . 4-153
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CONTENTS (continued)
4.2.2.8. Wigle (1977) 4-153
4.2.2.9. Lung Cancer Mortality Studies in
Louisiana ................ 4-155
4.2.2.9.1. Gottlieb et al. (1979) .... 4-155
4.2.2.9.2. Gottlieb (1980). ....... 4-157
4.2.2.9.3. Gottlieb and Carr (1981) . . . 4-159
4.2,2.10. Other Cancer Mortality Studies in
Louisiana ................ 4-161
4.2.2.10.1. Gottlieb and Carr (1981) . . 4-161
4.2.2.11. Brandt et al. (1978). 4-162
4.2.2.12. Plotnikov (1978). 4-163
4.3. EPIDEMIOLOGIC STUDIES IN PROGRESS. . . 4-164
4.3.1, Historical Prospective Mortality Study of Employees
Exposed to Downstream Gasoline in the Petroleum
Industry 4-164
4.3.2. Case-Control Study of Kidney Cancer and Hydrocarbon
Exposure Among Petroleum Company Workers ...... 4-165
4.3.3. Registry of Mortality of Refinery Workers. ..... 4-166
4.3.4. The Australian Petroleum Industry Health Watch
Surveillance Program 4-166
4.4. SUMMARY OF EPIDEMIOLOGIC STUDIES ........ 4-171
4.4.1. Summary of Epidemiologic Studies of Workers in the
Gasoline Service Industry. ............. 4-182
4.4.2. Summary of Epidemiologic Studies of Workers in the
Petroleum Refining Industry 4-188
4.4.3. Summary of Case-Control Studies That Evaluated Em-
ployment in the Petroleum Industry as a Risk Factor. 4-204
4.4.4. Summary of Epidemiologic Studies in Progress .... 4-206
4.4.5. Conclusions 4-207
5. QUANTITATIVE RISK ESTIMATION 5-1
5.1. PROCEDURES FOR THE DETERMINATION OF UNIT RISK. ....... 5-3
5.1.1. Low-Dose Extrapolation Model . 5-3
5.1.2. Selection of Data 5-6
5.1.3. Calculation of Human Equivalent Dosages. ...... 5-7
5.1.3.1. Oral 5-8
5.1.3.2. Inhalation ..... . 5-9
vi
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CONTENTS (continued)
5.1.3.2.1. Case 1 5-10
5.1.3.2.2. Case 2 ............ 5-11
5.1.4. Calculation of the Unit Risk from Animal Studies . . 5-12
5.2. LIFETIME RISK ESTIMATES 5-13
5.2.1. Data Available for Risk Estimation . ........ 5-13
5.2.2. Choice of Low-Dose Extrapolation Models. ...... 5-13
5.2.3. Calculation of Unit Risk (Risk at 1 ppm) ...... 5-16
5.2.4. Comparison of Risk Estimates by Different Low-Dose
Extrapolation Models ..... ..... 5-16
5.2.5. Uncertainties of Quantitative Risk Assessment. . . . 5-20
5.2.5.1. Uncertainties Associated with Potency
Estimates 5-20
5.2.5.2. Uncertainties Regarding the Assumption of
Carcinogenicity in Humans Based on Animal
Data 5-21
5.2.5.3. Uncertainties Associated with the Use of
Potency Estimates to Predict Individual
Risks in Real-Life Exposure Patterns . , . 5-22
5.2,5.4. Uncertainties Associated with Differences
in Composition of Gasoline Vapors and
Wholly Vaporized Gasoline. ........ 5-24
5.2.6. Cancer Risk Attributable to Benzene Content in Gaso-
line Vapor . 5-25
5.3. CONCLUSIONS OF THE HEALTH EFFECTS INSTITUTE (HEI) REGARDING
THE POTENTIAL ADVERSE HEALTH EFFECTS OF EXPOSURE TO GASOLINE
VAPORS . . .................... 5-26
5.4. SUMMARY OF QUANTITATIVE RISK ESTIMATION 5-27
6. REFERENCES ..... 6-1
APPENDIX A: COMPARISONS AMONG DIFFERENT EXTRAPOLATION MODELS
V11
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TABLES
3-1 Physicoehemical Characteristics of the Test Material. ..... 3-2
3-2 Formulation of Unleaded Gasoline 3-3
3-3 Inhalation Exposure Concentrations for a Carcinogenicity
Study on Unleaded Gasoline Vapor in Fischer 344 Rats and
B6C3F1 Mice ....... ..... 3-5
3-4 Body Weight Trends in a Carcinogenicity Study of Unleaded
Gasoline Vapor in Fischer 344 Rats 3-7
3-5 Body Weight Trends in a Carcinogenicity Study of Unleaded
Gasoline Vapor in B6C3F1 Mice 3-8
3-6 Effect of Chronic Exposure to Unleaded Gasoline Vapor on
Kidney Weights and Kidney/Body Weight Ratios In Male
Fischer 344 Rats 3-9
3-7 Kidney Tumor Incidence in Male Fischer 344 Rats from
Chronic Exposure to Unleaded Gasoline Vapor ... 3-12
3-8 Individual Data on Mineralization of the Renal Pelvis and
Kidney Tumors in Male and Female Fischer 344 Rats Exposed
to Unleaded Gasoline Vapor. 3-13
3-9 Hepatocellular Tumor Incidence in Female B6C3F1 Mice from
Chronic Exposure to Unleaded Gasoline Vapor .......... 3-15
3-10 Design of the 90-Day Inhalation Exposure Study 3-17
3-11 Summary of the Composition and Boiling Ranges of the
Test Materials. . 3-19
3-12 Nephrotoxic Effects in Rats Following a 21-Day Inhalation
Exposure to Light Straight-Run Naphtha . 3-20
3-13 Nephrotoxic Effects in Rats Following a 21-Day Inhalation
Exposure to Light Catalytic-Cracked Naphtha , . . 3-20
3-14 Nephrotoxic Effects in Rats Following a 21-Day Inhalation
Exposure to Light Catalytic-Reformed Naphtha 3-21
3-15 Nephrotoxic Effects in Rats Following a 21-Day Inhalation
Exposure to Heavy Catalytic-Reformed Naphtha. . . 3-21
3-16 Nephrotoxic Effects in Rats Following a 21-Day Inhalation
Exposure to Full-Range Alkylate Naphtha 3-22
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TABLES (continued)
3-17 Nephrotoxic Effects in Male Rats Following a Repeat 21-Day
Inhalation Exposure to Full-Range Alky!ate Naphtha. ...... 3-22
3-18 Nephrotoxic Effects in Rats Following a 21-Day Inhalation
Exposure to Polymerization Naphtha. ...... ... 3-23
3-19 Nephrotoxic Effects in Rats Following a 21-Day Inhalation
Exposure to an Unleaded Gasoline Blend 3-23
3-20 Nephrotoxic Effects in Rats Following a 90-Day Inhalation
Exposure to an Unleaded Gasoline Blend. ............ 3-24
3-21 Effects of 4 Weeks' Oral Exposure to Fractions of Unleaded
Gasoline . . 3-27
3-22 Effects of 4 Weeks' Oral Exposure to Organic Chemicals
Present in Gasoline (Series 1). ..... 3-28
3-23 Effects of 4 Weeks' Oral Exposure to Organic Chemicals
Present in Gasoline (Series 2) ..... 3-29
3-24 Biological Testing of Decalin, a Prototype Volatile
Hydrocarbon 3-31
3-25 Description of Fuel Inhalation Exposures. ........... 3-33
4-1 Summary of PMR Cancer Findings for Four Occupational
Categories with Gasoline or Petroleum Products Exposure . . . . 4-23
4-2 Summary of Cohort Characteristics from Four
Wen et al. Studies. 4-58
4-3 Comparison of Gottlieb's Original and Recalculated
Odds Ratios and Confidence Intervals for Lung Cancer
.Among All Males, by Age . 4-160
4-4 Summary of Epidemiologic Studies Reviewed ........... 4-172
4-5 Study Site Locations of Epidemiologic Studies Reviewed 4-178
4-6 Summary of Site-Specific Statistically Significant Cancer
Findings from Case-Control Studies that Evaluated Employment
in the Gasoline Service Industry as a Risk Factor ....... 4-184
4-7 Summary of Site-Specific Statistically Significant Cancer
Findings from Mil ham's 1983 Washington State PMR Study,
By Study Populations Exposed. ..... . . 4-186
ix
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TABLES (continued)
4-8 Summary of Site-Specific Statistically Significant Cancer
Findings from Cohort Mortality Studies that Evaluated Employ-
ment in the Petroleum Refinery Industry as a Risk Factor . . . 4-191
4-9 Summary of Site-Specific Statistically Significant Cancer
Findings from Cohort Mortality Studies that Evaluated Employment
in the Petroleum Refinery Industry as a Risk Factor 4-195
4-10 Summary of Site-Specific Statistically Significant Cancer
Findings from PMR Studies that Evaluated Employment in the
Petroleum Refinery Industry as a Risk Factor. ......... 4-196
4-11 Summary of Site-Specific Statistically Significant Cancer
Findings from Case-Control Studies that Evaluated Employment
in the Petroleum Industry as a Risk Factor 4-202
5-1 Incidence Rates of Total Kidney Tumors in Male Fischer 344
Rats Exposed to Unleaded Gasoline Vapor 5-14
5-2 Incidence Rates of Hepatocellular Tumors in Female B6C3F1 Mice
Exposed to Unleaded Gasoline Vapor 5-14
5-3 Estimates of Carcinogenic Potency Due to Exposure to 1 ppm
of Unleaded Gasoline Vapor 5-17
5-4 95% Upper-Bound (and Maximum Likelihood) Estimation of
Lifetime Risk at Various Dose Levels, Using Three Different
Low-Dose Extrapolation Models 5-18
A-l Maximum Likelihood Estimates of the Parameters for the Three
Extrapolation Models Based on Three Data Sets in API Unleaded
Gasoline Study , A-2
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PREFACE
The Carcinogen Assessment Group of the Office of Health and Environmental
Assessment has prepared this evaluation at the request of the Office of Air '
Quality Planning and Standards and the Office of Mobile Sources. The purpose
of the document is to review the available evidence regarding the carcinogen-
icity of gasoline vapors to people exposed to vapor emissions during refueling
of motor vehicles. This review characterizes the likelihood that gasoline
vapors are carcinogenic to exposed humans and provides an upper-bound quanti-
tative estimate of the human risk per unit of exposure. This information is
needed to assist the Agency in evaluating risk management options for reducing
the hazard from exposure to gasoline vapors. In the development of this
document the available scientific literature has been reviewed through 1985.
XI
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ABSTRACT
In this document the likelihood that unleaded gasoline vapors are carcino-
genic to humans is evaluated. From carcinogenicity data in animals, an estimate
1s made of the magnitude of cancer risk a person would experience, under the
assumption that gasoline vapors are carcinogenic. All biological factors
believed to be relevant to carcinogenesis are reviewed including: (a) chronic
and shorter-term animal studies of aerosolized whole gasoline, various gasoline
fractions, and analogous hydrocarbon mixtures; and (b) epidemiologic studies of
occupations involving exposure to gasoline vapors. Fifty-five epidemiologic
studies involving gasoline exposure are reviewed. A quantitative analysis of
cancer incidence in the two long-term animal gasoline inhalation studies is
performed, an upper-bound cancer risk potency estimate is calculated, and the
uncertainties in the estimate are discussed. The major conclusions are:
(1) although employment in the petroleum refineries is possibly associated
with cancers of the stomach, respiratory system, and lymphopoietic and hemato-
poletic tissues, exposure to gasoline cannot be implicated as a causative
agent because of confounding exposure to other chemicals and inadequate
information on gasoline exposure; (2) the occurrence of liver cancer in female
mice and kidney cancer in male rats provides "sufficient" evidence in animals
that Inhalation of wholly aerosolized gasoline is carcinogenic; and (3) gasoline
vapors from vehicle refueling might be less carcinogenic than indicated by
animal experiments using wholly aerosolized gasoline, if the less volatile
components, which are apparently responsible for acute kidney toxicity, also
contribute to the observed carcinogenic response.
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
This document was prepared by the Carcinogen Assessment Group within the
Office of Health and Environmental Assessment (William E. Pepelko, Project
Manager).
AUTHORS
Larry 0. Anderson*
Chao W. Chen
Vincent James Cogliano
Aparna M. Koppikar
Robert E. McGaughy
William E. Pepelko
D.E.B.. Potter* - .
REVIEWERS
David L. Bayliss
Carcinogen Assessment Group
Office of Health and Environmental Assessment
Michael A. Berry
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
Research Triangle Park, NC
Jerry N. Blancato
Exposure Assessment Group
Office of Health and Environmental Assessment
Herman J. Gibb
Carcinogen Assessment Group
Office of Health and Environmental Assessment
Vlasta Molak
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
Cincinnati, OH
Lawrence R. Valcovic
Reproductive Effects Assessment Group
Office of Health and Environmental Assessment
*0ffice of Drinking Water
i"Dynamac Corporation
xiii
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1. SUMMARY AND CONCLUSIONS
1.1. SUMMARY
1.1.1. Qualitative
1.1.1.1. Animal Studies—A lifetime inhalation bioassay of unleaded gasoline
in Fischer 344 rats and B6C3F1 mice has induced a statistically significant in-
creased incidence (6/100) of renal carcinomas in the kidney cortex of male rats
and a larger, also statistically significant, increase in the incidence (20/
100) of hepatocellular carcinomas in female mice. Female rats and male mice
had no significant treatment-related increase in tumors at any organ site. The
increase of renal carcinomas in male rats was statistically significant at the
highest dose tested (2,056 ppm) but not at the two lower doses (292 ppm and 67
ppm). However, the combined incidence of adenoma/carcinoma/sarcoma was also
significantly increased at the intermediate dose. In mice, the incidence of
liver carcinomas alone and adenoma and carcinoma combined was significantly
increased in the highest but not the two lower dose groups. Moderate decre-
ments in the body weight gain in the high-dose groups indicate that the maximum
tolerated dose was reached. Glomerulonephrosis occurred in nearly all of the
male rats, and mineralization of the pelvis was correlated with dose. However,
there was no correlation between animals with tumors and those with mineraliza-
tion.
The same pattern of glomerulonephritis, as well as positive tumor
responses, occurred with chronic inhalation exposure to synthetic fuels (RJ-5
and JP-10). Chronic inhalation studies with jet fuels used by the Air Force
and Navy (JP-4 and JP-5) have resulted in the same nephrotoxic lesions, but no
information is available about the carcinogenic response.
1-1
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In a series of exposures of male rats to a variety of distillate fractions
as well as to individual components of gasoline, toxicity was correlated with
the paraffin compounds present in the 145° to 280°F distillate fractions and
not with aromatic compounds in the mixture. The most toxic compounds were
branched-chain aliphatlcs, generally in the C6-C9 range, although some larger
molecules such as 2,2,4,4-tetramethyl octane also showed a high level of activ-
ity. The acute and subchronic renal toxicity of decalin, a volatile hydrocar-
bon of the same general type as those found in gasoline, is confined to male
rats and did not occur in female rats or in mice, dogs, or guinea pigs.
The renal toxicity pattern observed with exposure to hydrocarbon mixtures
involving protein accumulation in renal tubules is clearly different than the
kidney lesions occurring spontaneously in old rats, and occurs in males of both
Fischer 344 and Sprague-Dawley strains, but not in females of these strains or
in mice or monkeys. Mutagenesis tests of unleaded gasoline have been carried
out in Salmonella, yeast, mouse lymphoma in vivo cytogenetics, in mouse domi-
nant lethal systems, and in a rat kidney cell DNA repair model. Various gaso-
line feedstocks have been tested in mouse lymphoma and in viyo cytogenetics
assays. The results of most of these assays have not met the criteria for pos-
itive responses.
1.1.1.2. Epidemiologic Studies—Fifty-five studies were reviewed to determine
if there is any epidemic!ogic evidence for an association between gasoline
exposure and cancer risk. Since unleaded gasoline was only introduced in the
mid-1970s, even recent epidemiologic studies are not likely to show an unleaded
gasoline effect because of the long latency period generally associated with
cancer. Therefore, this review was not limited to unleaded gasoline exposure,
but addressed any potential gasoline exposure.
1-2
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None of the studies reviewed provided qualitative as well as quantitative
estimates of gasoline exposure.
Seven studies were identified that evaluated the association between em-
ployment in the gasoline service industry and cancer risks; the industry here
includes gasoline service station owners and attendants, garage workers, gaso-
line and fuel truck drivers, and those who reported working with gasoline. The
study by Stemhagen et al. (1983) provided some evidence of an association be-
tween gasoline service station employment and risk of primary liver cancer.
The remaining six studies were judged inadequate.
Twenty-five studies were reviewed that evaluated the association between
4
employment in a petroleum refinery (a work environment with potential gasoline
exposure) and cancer risk. Judged individually, these studies provided inade-
quate evidence of an association. However, judged collectively these studies
provide suggestive evidence of an association between employment in a petroleum
refinery and risk of stomach cancer, respiratory system cancer (i.e., lung,
pleura, nasal cavity, and sinuses), and cancer of the lymphatic and hematopoi-
etic tissues.
Nineteen case-control studies were reviewed which evaluated employment
in the petroleum industry as a cancer risk factor. The study by Howe et al.
(1980) provided limited evidence of an association between petroleum industry
employment and risk of bladder cancer.
Also reviewed were four protocols of epidemiologic studies in progress.
These studies may provide evidence of an association between gasoline exposure
and cancer risk; however, these findings are 3 to 5 years in the future.
1.1.2. Quantitative
Data from the API study on kidney tumors in male rats and liver adenomas
and carcinomas in female mice were used to derive an estimate of the incremen-
1-3
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tal upper-limit unit risk due to continuous human exposure to 1 ppm of unlead-
ed gasoline. Since the animals breathed an aerosol of whole gasoline under
laboratory conditions, whereas humans are expected to breathe only the more
volatile components of the mixture, the estimates are uncertain. If tumor
induction is caused by the same, relatively nonvolatile C6-C9 branched hydro-
carbons that are primarily responsible for the nephrotoxicity in male rats,
then the quantitative estimates of the risk of breathing gasoline vapors may
be overly conservative. The carcinogenic potency estimate for unleaded gaso-
line was derived from a continuous exposure study, whereas the actual human
exposure is periodic in most cases. The available information is not adequate
to determine if this will result in an overestimation or an underestimation of
risk. The estimates from the mouse and rat data are similar: 2.1 x 1Q~3 (ppm)"!
from mouse data and 3.5 x 10~3 (ppm)~l from rat data.
The presence of 2% benzene in the unleaded gasoline mixture could theoret-
ically contribute to the response, although the mouse liver and rat kidney have
not been the target organs in animal, experiments with benzene. Based on those
experiments, it is estimated that the contribution of benzene to the response
observed in the API unleaded gasoline studies could be on the order of 20%.
However, there is no qualitative evidence that benzene actually is contributing
to the response.
1.2. CONCLUSIONS
On the basis of a small but definite kidney tumor response in male rats
and a significant hepatocellular response in female mice, using EPA's Guide-
lines for Carcinogen Risk Assessment (U.S. EPA, 1986} to classify the weight of
evidence for carcinogenicity in experimental animals, there is sufficient
evidence to conclude that gasoline vapors are carcinogenic in animals. The
similar pattern of response in rats to the synthetic fuels RJ-5 and JP-10,
1-4
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and the renal toxicity observed in chronic bioassays with JP-4 and JP-5, sup-
port the findings with unleaded gasoline, indicating that some agent or com-
bination of agents common to these mixtures is responsible for the observed
effects.
The relevance of the rat kidney response to human carcinogenicity has been
questioned on the basis of experiments showing that early-occurring kidney
toxicity is apparently caused by the interaction of gasoline hydrocarbon
components with a unique protein ('alpha-2-microglobulin) produced in large
quantities only by the male rat and not other species. If this toxicity were
the cause of the kidney tumor response, the case for human carcinogenicity
would be weakened. However, given the current evidence, the Carcinogen Assess-
ment Group cannot disregard the rat kidney tumor response as an indication of
potential human carcinogenicity for several reasons: (a) the link between
hydrocarbon nephropathy and tumor induction is not proven; (b) with very few
exceptions, chemicals causing cancer in humans also cause cancer in animals,
indicating a similarity of response across the animal kingdom; and (c) the
kidney of experimental animals is a demonstrated target organ for more than
100 carcinogenic chemicals.
The EPA Science Advisory Board and the Health Effects Institute have
independently reviewed the earlier draft of this report. Both groups agreed
that the evidence for carcinogenicity in animals meets the EPA Guidelines
criteria for sufficient evidence in animals and inadequate evidence in humans.
They both pointed out the uncertain relevance of rat kidney tumors as an indi-
cation of human response and the difficulty in making quantitative estimates
of gasoline vapor potency from the animal study of whole gasoline when the
identity of the carcinogenic component is unknown.
1-5
-------
The epidemiologic studies collectively provide limited evidence that
occupational exposure in the petroleum industry is associated with certain
types of cancer. However, the evidence for evaluating gasoline as a potential
carcinogen is considered inadequate under the EPA Guidelines criteria for
epidemiologic evidence.
Based on sufficient evidence in animal studies and inadequate evidence in
epidemiologic studies, the overall weight of evidence for unleaded gasoline is
EPA category B2, meaning that unleaded gasoline is a probable human carcinogen.
The carcinogenic potency of unleaded gasoline, using data from the most
sensitive species tested, is 3.5 x 10~3 per ppm. This is a plausible upper
bound for the increased cancer risk from unleaded gasoline, meaning that the
true risk is not likely to exceed this estimate and may be lower.
1-6
-------
2. INTRODUCTION
This document presents an evaluation of the likelihood that unleaded
gasoline is a human carcinogen and provides a basis for estimating its possi-
ble public health impact, including a potency evaluation in relation to other
carcinogens. The evaluation of carcinogenicity depends heavily on animal
bioassays and epidemiologic evidence. However, other factors, including
mutagenicity, metabolism (particularly in relation to interaction with DNA),
k
and pharmacokinetic behavior have an important bearing on both the qualitative
and quantitative assessment of carcinogenicity. This document presents an
evaluation of the animal bioassays and relevant toxicity studies, the human
epidemiologic evidence, the quantitative aspects of assessment, and finally,
a summary and conclusions dealing with all of the relevant aspects of the
carcinogenicity of unleaded gasoline.
2-1
-------
-------
3. ANIMAL STUDIES
Although a number of experiments have been carried out to assess the acute
and subchronic toxicity of gasoline vapors, only one long-term study has been
conducted to date for the purpose of evaluating the carcinogenicity of unleaded
gasoline. This inhalation study, using Fischer 344 rats and B6C3F1 mice, was
conducted at the request of the American Petroleum Institute (API) and has been
published by MacFarland et al. (1984). This chapter contains a review by EPA's
Carcinogen Assessment Group (CAG) of the chronic inhalation study and other
studies related to the health impact of gasoline vapors or its constituents.
3.1. LIFETIME INHALATION BIOASSAY IN RATS AND MICE (INTERNATIONAL RESEARCH AND
DEVELOPMENT CORPORATION, 1983)
The following is a review of a final report of a study on the carcinoge-
nicity of unleaded gasoline vapor in Fischer 344 rats and B6C3F1 mice. The
study was completed by the International Research and Development Corporation
(IRDC) for the API in 1983 and has been published by MacFarland et al. (1984).
The physicochemical properties and the formulation of unleaded gasoline
test sample, as described by the sponsor, are presented in Tables 3-1 and 3-2.
The unleaded gasoline used in the API inhalation study was blended specifically
for the experiment. The test gasoline contained no EDB or EDC (as does leaded
gasoline). The benzene content of the test gasoline was 2.0%. In comparison
to commercial unleaded gasoline the test gasoline contained a higher proportion
of benzene (average percentage in commercial gasoline was 1.3 in 1977) and of
heavy catalytic-cracked naphtha (HCCN).
Exposures in the API animal inhalation study to the total gasoline vapor
were conducted in 16-m^ glass and stainless steel chambers. Humidity and tem-
perature within the chambers were approximately 55% and 25°C, respectively.
3-1
-------
TABLE 3-1. PHYSICOCHEMICAL CHARACTERISTICSa OF THE TEST MATERIAL
Research octane no. 92.0
Motor octane no. 84.1
(R+M)/2 88.1
Reid vapor pressure, Ibs. 9.5
Distillation, ASTM D-86
IBP, °F 93
10% evap., °F 116
50% evap., °F 216
90% evap., °F 340
End point, °F 428
API gravity 60.6
Gum, ASTM D381, mg/gal 1
Sulfur, ppm 97
Phosphorus, g/gal < 0.005
Lead, g/gal < 0.05
Stability, hours 24+
HC analysis, ASTM D1319
Aromatics, vol. % 26.1
Olefins, vol. % 8.4
Saturates, vol. % 66.5
Benzene content, vol. % 2.0
aAll of the above information was supplied by the sponsor, the American
Petroleum Institute.
SOURCE: IRDC, 1982.
3-2
-------
TABLE 3-2. FORMULATION OF UNLEADED GASOLINE
Generic stream3 CAS number Volume %
Light catalytic-cracked naphtha
Heavy catalytic-cracked naphtha
Light catalytic-reformed naphtha
Light alky! ate naphtha
Benzene added to bring to 2%
Butane added to increase Reid vapor
64741-55-5
64741-54-5
64741-63-5
64751-66-8
pressure
7.6
44.5
21.3
22.0
0.8
3.8
Plus: Antioxidant 5 lbs/1,000 bbl
Metal deactivator 5 lbs/1,000 bbl
aToxic Substance Control Act (TSCA) PL 94-469: Candidate List of Chemical
Substances, Addendum 1, Generic Terms Covering Petroleum Refinery Processed
Streams, January 1978.
3-3
-------
Gasoline vapor was generated by metering liquid through a heated vaporization
column; the vapor was carried by dry nitrogen to the inlet port of the chamber,
where the vapor was diluted with filtered air at a flow rate of 910 to 1,900
L/min to achieve the desired atmospheric concentrations.
Exposure concentrations are given in Table 3-3. Actual concentrations,
measured by gas chromatography, and nominal concentrations approximated desired
concentrations rather closely.
The same protocol was used for the study in rats and mice. Rats and mice
were about 6 weeks old when the study began. Initial body weights were: male
rats, 95 to 129 g; female rats, 79 to 105 g; male mice, 14 to 26 g; female-
mice, 12 to 20 g. Animals were randomly assigned to exposure groups according
to body weight. Three treatment groups, each composed of 100 males and 100
females, were exposed to measured levels of 67, 292, or 2,056 ppm of gasoline
vapor. An untreated group of 100 males and 100 females was exposed to filtered
chamber air only. Animals were exposed 6 hours/day, 5 days/week until final
sacrifice at 107 weeks (male rats and male mice), 109 weeks (female rats), and
113 weeks (female mice). Ten males and 10'females per group were sacrificed at
3, 6, 12» and 18 months.
Animals were observed daily, and body weights were recorded monthly for the
first 17 months and biweekly thereafter. Hematology was evaluated for seven
males and seven females per group at 18 and 24 months. Serum from seven males
and seven females per group was biochemically analyzed at 3t 6, 12, 18, and 24
months. Ten animals from each dose/sex group were killed after 3, 6, 12, and
18 months of exposure to provide for periodic histopathologic evaluation.
Survivors, interim sacrificed animals, and decedents were necropsied, and
tissues, organs, and tumors were examined microscopically. Major organs were
wei ghed.
3-4
-------
TABLE 3-3. INHALATION EXPOSURE CONCENTRATIONS FOR A CARCINOGENICITY
STUDY ON UNLEADED GASOLINE VAPOR IN FISCHER 344 RATS
AND B6C3F1 MICE
Exposure
group
Low
Mid
High
Desired
concentration
(ppm)
50
275
1,500
Nominal
concentration3
(ppm)
129
596
2,963 .
Actual
concentration3
(ppm)
49.7
273
1,501
aThe actual concentration data have not been corrected for the "nitrogen
effect" on instrument calibration. Furthermore, an error in chamber airflow
rate calibrations was reported which increased the actual airflow rate to
approximately twice the assumed flow rate. If the corrections discussed in
the study report are applied, the most probable nominal and actual concentra-
tions were as follows:
Nominal Actual
Exposure concentration concentration
group (ppm) (ppm)
Low 72 67
Mid 310 292
High 1,713 2,056
SOURCE: IRDC, 1982.
3-5
-------
Exposure to unleaded gasoline vapor did not affect survival. All groups
of rats and female mice had greater than 50% survival for the entire study,
and survival for all groups of male mice was greater than 50% for at least 95
weeks.
Body weight trends are given in Tables 3-4 and 3-5. Modest reduction of
weight gain was found in male and female rats and male mice in the high-dose
groups. No effect of gasoline vapor on weight gain in female mice was ob-
served.
Organ weights (absolute and organ/body) did not appear to be affected by
treatment with gasoline vapor, with the exception of significant (p < 0.05)
increases in kidney weights and kidney/body weight ratios in high-dose male
rats, as shown in Table 3-6.
At the 3-month interim sacrifice, dose-related nonneoplastic histopatho-
logic changes were observed in the male rats. These consisted of cortical
multifocal renal tubular basophilia, protein casts, and chronic interstitial
inflammation. The basophilia was present in epithelial cells of renal tubules.
The proteinaceous tubular casts occurred within dilated renal tubules and were
commonly located at the corticomedullary junction. The incidence was 70 and
100% in mid- and high-dose males, respectively. Chronic interstitial inflam-
matory foci with a predominantly lymphoid cell type were observed at 20 and 70%
incidence in mid- and high-dose males, respectively. In addition, renal con-
gestion and very small foci of renal cortical mineralization were noted in
several rats.
In animals dying in the 3- to 6-month interval or sacrificed at 6 months,
the nonneoplastic renal changes in male rats described above were again evident.
The incidence of tubular basophilia was 0%, 40%, 100%, and 100% in control-, low-,
mid-, and high-dose male rats, respectively. Proteinaceous casts were observed
3-6
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TABLE 3-4. BODY WEIGHT TRENDS IN A CARCINOGENICITY STUDY OF
UNLEADED GASOLINE VAPOR IN FISCHER 344 RATS
Study week
Males
0
13
26
52
78
106
\
Femal es
0
13
26
52
78
108
Control
112 + 8
306 + 18
348 + 19
409 + 27
401 + 31
416 +_ 29
93 + 6
173 + 11
209 + 12
250 +18
264 + 19
288 + 35
Mean
67 ppm
113 + 8
316 + 15b
361 + 19b
412 + 27
406 + 41
403 + 44
93 + 6
186 + llb
210 + 11
256 + 16a
274 + 19a
282 + 31
body weight + S.D.
292 ppm
113 + 9
312 + 16a
350 + 20
398 + 24a
393 + 20
388 +_ 33
92 + 6
177 + 12a
201 + 12b
249 + 18
263 + 21
289 + 48
(grams)
2,056 ppm
112 + 8
290 + 18b
340 + 16b
376 + 20b
376 + 25b
364 +_ 32
92 + 6
173 + 9
192 + 10b
225 + 13b
246 + 16b
255 + 27
^Statistically different from control group at p <_ 0.05.
Statistically different from control group at p _< 0.01.
SOURCE: Adapted from IRDC, 1982.
3-7
-------
TABLE 3-5. BODY WEIGHT TRENDS IN A CARCINOGENICITY STUDY OF
UNLEADED GASOLINE VAPOR IN B6C3F1 MICE
Study week
Males
0
13
26
52
78
102
Females
0
13
26
52
78
112
Control
22 + 2
30+2
33+2
38+4
38 T 4
39 T 4
18 + 2
25+1
28 + 1
31 + 3
35 + 3
34 + 3
Mean
67 ppm
21+2
29 + 2
32 T2a
36 T 3b
37 T 4
37 T 5
18 + 2
25 + 1
28 + 2
32 + 4
35 + 5
35 + 4
body weight + S.D.
292 ppm
22 + 2
31 + 2b
32 + 2*
35 + 3b
37 T33
38 T 3
18 + 2
26 + ia
28 + 1
30 + 2
34 + 3b ,
34 + 3
(grams)
2,056 ppm
22 + 2
31 + 2
34 T 2a
35 + 3b
35 + 3b
35+3
18 + 2
26 + lb
29 + 2
30 + 2a
32 + 3b
32 + 3
^Statistically different from control group at p _< 0.05.
"Statistically different from control group at p _< 0.01.
SOURCE: Adapted from IRDC, 1982.
3-8
-------
TABLE 3-6. EFFECT OF CHRONIC EXPOSURE TO UNLEADED GASOLINE VAPOR ON KIDNEY WEIGHTS
AND KIDNEY/BODY WEIGHT RATIOS IN MALE FISCHER 344 RATS
CO
10
Kidney
weights and kidney/body weight ratios
Dose group
Weight
measured
Ki dney
Kidney/ body
Kidney
Kidney/ body
Kidney
Kidney/ body
Kidney
Kidney/ body
Kidney
Kidney/ body
Month
of study
3
3
6
6
12
12
18
18
24
24
0 ppm
2.39J:
8.19 +
2.62 +_
7.87 ^
3.07 +
8.02^
2.70 +_
6.94 +
2.80 +_
6.93 +_
(control)
0.32a(10)b
0.80 (10)
0.32 (10)
0.55 (10)
0.19 (10)
0.55 (10)
0.19 (10)
0.49 (10)
0.33 (26)
0.95 (26)
67 ppm
2.39 +
7.82 +
2.71 +
7.76 +
3.13 +
7.94 _+
2.64 +_
7.26^
2.91 +
7.38 j+
0.32
0.80
0.26
0.64
0.19
0.40
0.19
1.18
0.34
1.09
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(38)
(38)
272 ppm
2.41 +
8.13^
2.64 +_
8.03 +
3.30 +_
8.29^
2.73 +_
7.37 ±
2.87 +_
7.55 +_
0.20
0.54
0.16
0.36
0.32
0.31
0.13
0.51
0.24
0.71C
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(34)
(34)
2,056 ppm
2.70 + 0.24C
9.35 JH 0.49d
2.84 +_ 0.17
8.86 + 0.39^
3.13 +_ 0.38
8.78^ 0.74d
2.80 +_ 0.11
7. 83 1 0.44d
3.13 +_ 0.34d
8.75 + 1.01d
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(32)
(32)
aMean +_ S.D.
bNumber of animals evaluated.
cStatistically, significant difference compared to control group (p £0.05).
^Statistically significant difference compared to control group (p <_0.01).
SOURCE: IRDC, 1982.
-------
in 27% of the control male rats, 801 of the mid-dose male rats, and 100% of the
high-dose male rats. The Incidence of chronic interstitial inflammation was
18, 20, 100, and 100% in control, low-, mid-, and high-dose male rats, respec-
tively. Mineralization in a radial pattern within the renal pelvis, with
material located within tubules or the collecting ducts of the renal pelvis,
was observed in 20% of the high-dose males.
At the 12-month Interim sacrifice, the occurrence of proteinaceous casts
in the kidneys of male rats was nearly equal in all groups: 20%, 30%, 30%, and
30% in control, low-, mid-, and high-dose male rats, respectively. Mineraliza-
tion in the renal pelvis occurred in 20% of the mid-dose male rats and in 80%
of the high-dose male rats. Progressive glomerulonephrosis was diagnosed in
one high-dose male rat. Another new finding was karyomegaly (very large nuclei
within renal tubular epithelial cells) in male rats.
The complexity of nonneoplastic morphologic alterations observed in the
kidneys of all rats, especially males, increased after 18 months of exposure.
Progressive glomerulonephrosis occurred with higher incidence than previously.
The lesion was characterized by atrophied or sclerosed glomeruli, dilated renal
tubules containing proteinaceous casts, tubular damage with regeneration or
scarring, and the presence of foci of chronic inflammatory cells. The incidence
of glomerulonephrosis in male rats was 20% in controls, 30% in the mid-dose
group, and 20% in the high-dose group; the incidence in female rats was slight-
ly lower. Proteinaceous casts in the kidneys of male rats were noted in 50,
50, 40, and 60% of control, low-, mid-, and high-dose male rats, respectively.
Mineralization in the renal pelvis was seen in 20% of the mid-dose and 80% of
the high-dose male rats. Renal congestion was commonly seen, and karyomegaly
was again noted in male rats. A benign renal cortical adenoma was diagnosed in
a high-dose male rat. Mononuclear cell leukemia was diagnosed in the kidney of
3-10
-------
a female rat that died during the 12- to 18-month interval.
At the final sacrifice, nearly all male rats exhibited progressive glo-
merulonephrosis. The incidence rates were 100, 95, 97, and 100% in control,
low-, mid-, and high-dose male rats, respectively. A slightly lower rate of
occurrence was seen in female rats. Mineralization in the renal pelvis occurred
in 0, 5, 63, and 91% of the control, low-, mid-, and high-dose males, respec-
tively. Karyomegaly was observed occasionally in the male rats. One mid-dose
male rat had renal tubular epithelial hyperplasia at termination. The lesion
was characterized by the presence of a large dilated tubule containing a cystic
lumen lined by epithelial cells. Renal cysts, epithelial cell pigmentation,
hydronephrosis, chronic interstitial inflammation, congestion, cortical and
pelvic mineralization in female rats, and necrosis were among the nonneoplastic
lesions observed in the 18-month to terminal sacrifice period.
Pathologic examination of the rats revealed a small incidence of renal
tumors in each treated group of male rats (Table 3-7). The first of these
tumors was detected at the 18-month interim kill. Renal carcinomas were found
in each treated group of male rats, with those in high-dose males being signi-
ficantly (p < 0.05) increased compared to controls (Table 3-7). A statistical
test for linear trend was significant at the 0.05 level. Among females, one
renal "sarcoma was reported in the mid-dose group. Renal carcinomas generally
consisted of epithelial cells in a tubular or acinar pattern in the cortex, and
renal adenomas mainly included small masses of epithelial cells forming tubular
or papillary structures in the cortex. Renal sarcomas consisted primarily of
spindle cells in a more pelvic location. The following percentages of final
sacrificed male rats had mineralization of the renal pelvis: control, 0%;
low-dose, 5%; mid-dose, 63%; high-dose, 91%. Mineralization of the renal pel-
vis was not found in each kidney with a tumor (Table 3-8); hence, mineraliza-
3-11
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TABLE 3-7. KIDNEY TUMOR INCIDENCE IN HALE FISCHER 344 RATS FROM CHRONIC EXPOSURE
TO UNLEADED GASOLINE VAPOR
Tumor type
Exposure group (ppm gasoline vapor)
0 (control)
67
292
2,056
Time to
first tumor (day)
CO
I
Renal adenoma/ 0/100a
adenoma cortex
Renal carcinoma/ 0/100b
renal carcinoma
undifferentiated
0/100
1/100C
2/100
2/100
1/100
6/10ocsd,e
546
692
Renal sarcoma'
Total
0/100
0/100b
0/100
1/100
1/100
5/100d»e
0/100
7/100c»d»e
748
aNumber with tumor/number examined.
Statistical analysis for linear trend was significant at the 0.05 level.
cln the IRDC (1982) interim report, renal carcinomas were diagnosed in 2 low-dose and 5 high-dose
male rats. Further analysis of the kidney sections, as indicated in the subsequent final report
on the study, resulted in the observation of renal carcinomas in 1 low-dose and 6 high-dose male
rats.
dThe 100 animals in each denominator in this table include 40 animals sacrificed at 3, 6, 12, and
18 months, and decedents and survivors in the remaining 60 animals which were allowed to survive
for the duration of the study. If the 40 interim sacrificed animals are excluded from each denom-
inator to allow replacement of the 100 total animals with the 60 animals allowed to survive for
the duration of the study, the statistically significant differences shown in this table remain
significant at p < 0.05.
eStatistically significant (p < 0.05) increase compared to control group by Fisher Exact Test.
^A renal sarcoma was also found in a female rat in the 292-ppm exposure group.
SOURCE: IRDC, 1982; MacFarland et al., 1984.
-------
TABLE 3-8. INDIVIDUAL DATA ON MINERALIZATION OF THE RENAL PELVIS
AND KIDNEY TUMORS IN MALE AND FEMALE FISCHER 344 RATS
EXPOSED TO UNLEADED GASOLINE VAPOR8
Dose group
Rat
identi-
fication
number'3
Kidney
tumor type
(grade)bc
Renal
pelvis
mineral-
ization ( grade )c
Males
67 ppm
272 ppm
2,056 ppm
Females
292 ppm
1339
1442
1381
1447
1420
1380
1467
1550
1481
1490
1506
1544
1501
1842
Carcinoma (3)
Carcinoma (2)
Carcinoma,
undiffer-
entiated (0-4)
Sarcoma (4)
Adenoma (3)
Adenoma (2)
Carcinoma
Carcinoma
Carcinoma
Carcinoma
Carcinoma,
undiffer-
entiated (3)
Carcinoma,
undiffer-
entiated (3)
Adenoma, cortex
Sarcoma (0-4)
(3)
(2)
None
None
None
None
Present (1)
Present (3)
Present (3)
None
Present (3)
Present (3)
Present (2)
Present (3)d
Present (2)
None
aThese data are taken from the IRDC (1982) report except where indicated.
^These data represent the final review of the kidney slides as presented by
Kitchen (1983) at the Workshop on the Kidney Effects of Hydrocarbons.
cGrading system: 1 = very slight
2 = slight or small
3 = moderate
4 = severe
"Mineralization located in renal cortex instead of renal pelvis.
3-13
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tlon of the renal pelvis does not appear to have been a requirement in the
etiology of kidney tumor formation in rats exposed to unleaded gasoline vapor.
Spontaneous kidney tumor formation is rare in male Fischer 344 rats; for
example, Goodman et al. (1979) reported a historical control incidence of one
kidney adenoma (0.05%), two kidney adenocarcinomas (0.11%), and three benign
mixed kidney tumors (0.17%), for a total of six kidney tumors (0.33%) formed
spontaneously in 1,794 untreated Fischer 344 rats evaluated in the National
Cancer Institute's Carcinogenesis Testing Program from 1972 through 1978. The
historical control incidence of 0.11% reported by Goodman et al. (1979) is
20-fold less than the 2% incidence of kidney adenocarcinomas in low-dose males
shown in Table 3-7.
A significantly (p < 0.01) increased incidence of hepatocellular carcinomas
alone and of hepatocellular adenomas and carcinomas combined was found in high-
dose female mice as compared to control mice (Table 3-9). Except for a hepato-
cellular carcinoma in a high-dose female mouse that died at between 12 and 18
months, the observation of hepatocellular adenomas and carcinomas in female
mice, as shown in Table 3-9, was confined to those animals necropsied from 18
months through final sacrifice. Hepatocellular carcinomas were described as
having invasive, trabecular, and solid patterns with areas of necrosis and
cytoplasmic vacuolization. Macroscopic findings in the liver of male and
female mice included lobulated masses of raised red firm foci which correlated
with histopathologic diagnoses of adenomas and carcinomas in liver. Mucoserous
nasal discharge, possibly related to an irritant effect of gasoline vapor, was
noted for male and female high-dose mice. A papillary cystic adenoma of the
renal cortex was found in a high-dose female mouse killed at final sacrifice,
and bilateral renal tubular adenocarcinomas were found in a high-dose female
mouse which died in the period between 18 months and final sacrifice.
3-14
-------
TABLE 3-9. HEPATOCELLULAR TUMOR INCIDENCE IN FEMALE B6C3F1 MICE
FROM CHRONIC EXPOSURE TO UNLEADED GASOLINE VAPOR
HepatocelluTar
tumor type
0 (control)
Exposuregroup (ppm gasoline vapor)
67 292 2,056
Adenoma 1/10Q3
Carcinoma 7/100
Adenoma and carcinoma 8/100
combined
4/100
6/100
10/100
3/100
9/100
12/100
7/100
20/100b»c
27/100b»c
^Number with tumor/number examined.
"Statistically significant (p < 0.01) increase compared to control group.
cThe 100 animals in each denominator in this table includes 40 animals sacri-
ficed at 3» 6, 12, and 18 months and decedents and survivors in the remaining
60 animals which were allowed to survive for the duration of the study. If
the 40 interim sacrificed animals are excluded from each denominator to allow
replacement of the 100 total animals with the 60 animals allowed to survive
for the duration of the study, the statistically significant differences shown
in this table remain significant at p < 0.01.
SOURCE: IRDC, 1982.
3-15
-------
In summary, exposure to unleaded gasoline vapor produced a small but sta-
tistically significant (p < 0.05) increase in renal carcinomas in male Fischer
344 rats, and a statistically significant increase (p < 0.01) in hepatocellu-
lar carcinomas in female B6C3F1 mice under the conditions of this bioassay.
Moderate body weight gain decreases with no reduction in survival in high-dose
groups suggest that a maximum tolerated dose was approached; however, mineral-
ization in the kidney indicates that exposure to unleaded gasoline vapor pro-
duced toxicity in this organ in each treated group of male rats. Applying the
International Agency for Research on Cancer (IARC) classification approach for
carcinogens, as well as EPA's Guidelines for Carcinogen Risk Assessment (U.S.
EPA, 1986), the EPA's Carcinogen Assessment Group (CAS) concludes that these
studies furnish sufficient evidence for the cardnogenicity of unleaded gaso-
line vapor in animals under the conditions of the bioassay.
3.2. 90-DAY INHALATION EXPOSURE STUDY WITH GASOLINE VAPOR IN RATS AND MONKEYS
(MacFARLAND, 1983)
A 90-day inhalation exposure study of the toxicity of unleaded gasoline
vapor in Sprague-Dawley rats and squirrel monkeys was performed as a prechronic
test in preparation for the carcinogenicity study with unleaded gasoline in
rats and mice. In the 90-day study, rats and monkeys were exposed 6 hours/day,
5 days/week for 13 weeks to totally vaporized unleaded EPA reference gasoline
and a leaded commercial gasoline, as shown in Table 3-10. The hydrocarbon com-
position of the two gasolines was similar, but the unleaded gasoline contained
5 mg/gallon of lead and the leaded gasoline contained 1.94 g/gallon of lead.
The animals were examined for mortality, body weight, food consumption, toxic
signs, hematological changes, urinary changes, tissue lead levels, and pathol-
ogy. Pulmonary function tests and cortical flash-evoked response tests were
also done on the monkeys.
3-16
-------
TABLE 3-10. DESIGN OF THE 90-DAY INHALATION EXPOSURE STUDY
Number3 and species of animals
Concentration
group
I. Control
•II. Unleaded gasoline
III. Unleaded gasoline
IV. Leaded gasoline
V. Leaded gasoline
Rats
40
40
40
40
40
Monkeys
8
8
.8
8
8
Dose (ppm)
0
384
1,552
103
374
aEqually divided as to sex.
Some female monkeys in Groups III and V showed emesis. Body weights in
male rats in Groups II and IV were significantly greater at termination.
Female rats in Group III had increased reticulocyte counts, and some rats in
Group V had increases in hematocrit and mean corpuscular volume, and decreases
in white cell count and mean corpuscular hemoglobin concentration.
Male monkeys in Groups III and V had an increased minute volume. Female
monkeys in Group III had a reduced respiratory rate, and female monkeys in
Group V had a decreased tidal volume at termination.
Liver weights were increased in male rats in Groups II and IV and decreased
in Group V female rats. Kidney weights were increased in Group IV female rats
and Group V male monkeys. Thyroid weights were increased in male monkeys in
Groups II and III. Heart/body weights were decreased in male rats in Groups IV
and V, and brain weights were decreased in male rats in Groups II and III.
Group V female rats had decreases in liver/body and adrenal/body weights.
3-17
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The initial pathological examinations showed no treatment-related effects.
Hlstopathologic reexamination of tissue sections showed subtle but discernible
changes in kidneys of Group III male rats. These changes were described as an
increase in the incidence and severity of regenerative epithelium, and protein-
aceous material in dilated tubules was found.
3.3. RENAL TOXICITY OF GASOLINE AND RELATED PETROLEUM NAPHTHA IN MALE RATS
(HALDER ET AL.f 1984)
The renal effects of subchronic inhalation exposure of male and female
Sprague-Dawley rats to wholly vaporized unleaded gasoline and related petro-
leum naphthas described in Table 3-11 were reported by Haider et al. (1984).
The results of this study are presented in Tables 3-12 through 3-20. This
study is especially pertinent to the unleaded gasoline carcinogenicity study
in that it gives an indication as to which fractions in unleaded gasoline can
produce kidney toxicity.
Exposure of male and female Sprague-Dawley rats to unleaded gasoline for
21 days induced mild tubular degenerative and regenerative changes with in-
creases in hyalin droplets in the renal cortex in males. Corticomedullary
tubular dilatation and necrosis were found in one high-dose male rat.
A 90-day exposure to unleaded gasoline resulted in a treatment-related
incidence of tubular dilatation and necrosis at the corticomedullary junction
in male rats, along with a dose-related severity. The persistence of these
lesions during a 4-week recovery period suggests an irreversible effect.
Similar 21-day exposures of rats to full-range alky!ate naphtha, polymer-
ization naphtha, light catalytic-reformed naptha, and light straight-run naph-
tha induced renal lesions in males similar to those obtained with unleaded
gasoline treatment. Milder renal lesions were found in males exposed to light
catalytic-cracked naphtha. No renal effects were noted with exposure to heavy
3-18
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TABLE 3-11. SUMMARY OF THE COMPOSITION AND BOILING RANGES
OF THE TEST MATERIALS
Composition (%)
Material Paraffins3
Light straight-run
naphtha
Light catalytic-cracked
naphtha
Light catalytic-reformed
naphtha
Heavy catalytic-reformed
naphtha
Full -range alkylate
naphtha
Polymerization naphtha
Unleaded gasoline blend
96
39
67
7
98
8
45b
Olefins Aromatics
0 4
32 29
2 31
0 93
2 0
92 <1
12b 43b
Boiling
10% bp
71
174
137
290
124
205
112
range (°F)
90% bp
222
346
230
364
315
353
326
alncludes cyclo-, normal, and branched.
^Estimated.
3-19
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TABLE 3-12. NEPHRQTOXIC EFFECTS IN RATS FOLLOWING A 21-DAY INHALATION
EXPOSURE TO LIGHT STRAIGHT-RUN NAPHTHA
Incidence^
Group and
concentration3 M F
Environmental control 0/10 0/10
Sham control 0/10 0/10
1.50 mg/L (395 ppm) 0/10 0/10
5.13 mg/L (1,349 ppm) 0/10 0/10
14.56 mg/L (3,829 ppm) 3/10 0/10
Analytical time-weighted average in mg/L (ppm).
^Incidence of tubular dilation and necrosis at corticomedullary junction,
TABLE 3-13. NEPHROTOXIC EFFECTS IN RATS FOLLOWING A 21-DAY INHALATION
EXPOSURE TO LIGHT CATALYTIC-CRACKED NAPHTHA
Group and
concentration3 Effects
Sham control
0.20 mg/L (43 ppm)
Evidence of early
2.04 mg/L (434 ppm) degenerative changes in
kidneys of treated male rats,
13.06 mg/L (2,777 ppm)
Analytical time-weighted average in mg/L (ppm).
3-20
-------
TABLE 3-14. NEPHROTOXIC EFFECTS IN RATS FOLLOWING A 21-DAY INHALATION
EXPOSURE TO LIGHT CATALYTIC-REFORMED NAPHTHA
Incidence13
Group and
concentration3 M
Environmental control 0/10 0/10
Sham control 0/10 0/10
2.00 mg/L (544 ppm) 0/10 0/10
5.85 mg/L (1,591 ppm) 1/10 0/10
20.30 mg/L (5,522 ppm) 3/10 0/10
Analytical time-weighted average in mg/L (ppm).
''Incidence of tubular dilation and necrosis at corticomedullary junction,
TABLE 3-15. NEPHROTOXIC EFFECTS IN RATS FOLLOWING A 21-DAY INHALATION
EXPOSURE TO HEAVY CATALYTIC-REFORMED NAPHTHA
Incidence*3
Group and
concentration3 M F
Environmental control 0/10 0/10
Sham control NEC NE
1.03 mg/L (215 ppm) NE NE
2.81 mg/L (587 ppm) 0/10 0/10
10.20 mg/L (2,132 ppm) 0/10 0/10
Analytical time-weighted average in mg/L (ppm).
blncidence of tubular dilation and necrosis at corticomedullary junction.
CNE = Not examined. Pathology was not done due to lack of adverse effects
at higher concentrations.
3-21
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TABLE 3-16. NEPHROTOXIC EFFECTS IN RATS FOLLOWING A 21-DAY INHALATION
EXPOSURE TO FULL-RANGE ALKYLATE NAPHTHA
Incidence^
Group and
concentration9 M F
Environmental control 0/10 0/10
Sham control 0/10 0/10
1.54 mg/L (345 ppm) 10/10 0/10
4.92 mg/L (1,104 ppm) 10/10 0/10
15.31 mg/L (3,434 ppm) 10/10 0/10
^Analytical time-weighted average In mg/L (ppm).
blncidence of tubular dilation and necrosis at cortlcomedullary junction.
TABLE 3-17. NEPHROTOXIC EFFECTS IN MALE RATS FOLLOWING A REPEAT 21-DAY
INHALATION EXPOSURE TO FULL-RANGE ALKYLATE NAPHTHA
Group and Incidence
concentration3 in males'5
Sham control 0/40
0.015 mg/L (3 ppm) 0/20
0.152 mg/L (34 ppm) 4/10
1.538 mg/L (345 ppm) 11/20
^Analytical time-weighted average in mg/L (ppm).
^Incidence of tubular dilation and necrosis at cortlcomedullary junction,
3-22
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TABLE 3-18. NEPHROTOXIC EFFECTS IN RATS FOLLOWING A 21-DAY INHALATION
EXPOSURE TO POLYMERIZATION NAPHTHA
Incjdencej3
Group and
concentration9 M F
Environmental control 0/10 0/10
Sham control 0/10 0/10
1.04 mg/L (215 pptn) 0/10 0/10
3.05 mg/L (632 ppm) 2/10 0/10
9.89 mg/L (2,049 ppm) 4/10 0/10
Analytical time-weighted average in mg/L (ppm).
b Incidence of tubular dilation and necrosis at corticomedullary junction,
TABLE 3-19. NEPHROTOXIC EFFECTS IN RATS FOLLOWING A 21-DAY
INHALATION EXPOSURE TO AN UNLEADED GASOLINE BLEND
Incidence^
Group and
concentration3 M F
Environmental control 0/10 0/10
Sham control 0/10 0/10
0.11 mg/L (29 ppm) , 0/10 0/10
1.58 mg/L (416 ppm) 0/10 0/10
12.61 mg/L (3,316 ppm) 1/10 0/10
^Analytical time-weighted average 1n mg/L (ppm).
"Incidence of tubular dilation and necrosis at corticomedullary junction,
3-23
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TABLE 3-20. NEPHROTOXIC EFFECTS IN RATS FOLLOWING A 90-DAY
INHALATION EXPOSURE TO AN UNLEADED GASOLINE BLEND
Incidence^3
Group and
concentration3
Envi ronmental control
Sham control
0.15 mg/L (40 ppm)
1.44 mg/L (379 ppm)
14.70 mg/L (3,866 ppm)
Terminal
M
0/10
0/10
1/10
7/10
5/10
sacrifice
F
0/10
0/10
0/10
0/10
0/10
Four-week
M
0/10
0/10
1/10
5/10
4/10
recovery
F
0/10
0/10
0/10
0/10
0/10
^Analytical time-weighted average in mg/L (ppm).
"Incidence of tubular dilation and necrosis at corticomedullary junction.
3-24
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catalytic-reformed naphtha.
The results of these studies suggest that paraffin and alkene fractions
are effective as renal toxicants and that aromatics are relatively nontoxic.
The unleaded gasoline blend included some of the naphtha materials tested in
this study, and although the unleaded gasoline composition is proprietary, it
was mentioned that it contained 22% full-range alkylate naphtha, a fraction
which could be a significant factor in. renal toxicity induced by unleaded gas-
oline exposure.
3.4. TOXICITY OF ORGANIC CHEMICALS PRESENT IN UNLEADED'GASOLINE
In order to more accurately determine which compounds present in unleaded
gasoline are the primary sources of nephrotoxicity in rats, a series of studies
sponsored by the American Petroleum Institute were carried out. Unleaded gas-
oline was distilled into 0° to 145°F, 145° to 220°F, 220° to 280°F, and 28Q°F+
fractions. Each of these fractions, as well as the individual aliphatic hydro-
carbons comprising the major portion of each fraction, were evaluated in a
series of subchronic studies. The individual studies are described below.
3.4.1. 13-Week Inhalation Toxicity Study of a 0° to 145°F Gasoline Distillate
Fraction 1n Rats (IIT Research Institute, 1985a)
Fischer 344 rats of both sexes were exposed to a 0° to 145°F gasoline dis-
tillate fraction 6 hours/day, 5 days/week via inhalation over a 13-week period.
The concentration was maintained at 1,000 or 4,500 ppm. No evidence of hydro-
carbon nephropathy or other toxic signs were detected in either male or female
rats.
3.4.2. 13-Week Inhalation Toxicity Stuciy of C4/C50 Hydrocarbon Blends in Rats
(IIT Research Institute, 1985b)
Fischer 344 rats were exposed to the same concentrations under the same
experimental conditions as those in the previous study. Two vapor mixtures
3-25
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were used. One was a 50:50 mixture of n-butane and n-pentane. The other was
a 50:50 mixture of isobutane and isopentane. These four chemicals comprise
over 70% of the hydrocarbons present in the 0° to 145°F distillate fraction of
unleaded gasoline. The exposure-related effects were nominal with no evidence
of hydrocarbon nephropathy.
3.4.3. Renal Toxicity of Whole Unleaded Gasoline, Fractions of Unleaded Gas-
oline, Various Naphthas, and Some Individual Components, in Male Rats
(Haider et al., 1984)
This study was designed to evaluate, in greater detail, the components of
unleaded gasoline in the less volatile fractions responsible for the induction
of renal toxicity in rats. Test materials included whole unleaded gasoline,
145° to 220°F, 220° to 280°F, 280°F+ distillate fractions, four naphthas, and a
variety of individual organic components. Fischer 344 male rats were exposed
to the test materials via oral gavage at 0.5 or 2.0 mg/kg/day, 5 days/week for
4 weeks. The kidneys were scored for three types of lesions, hyaline droplet
formation, regenerative epithelium, and tubular dilation with granular material.
The lesions were graded on a severity of 1 to 5, with the scores for the three
lesions added, then summed over 10 animals per group.
The results are listed in Tables 3-21, 3-22, and 3-23. Of the individual
compounds tested, straight-chain alkanes and alkenes, cyclic alkanes, and
aromatics were relatively nontoxic. The most toxic compounds were aliphatic
hydrocarbons in the C6-C9 range with multiple branching. Of the chemicals
tested, 2,2,5-trimethylpentane and 2,2,5-trimethylhexane were the most active.
Since the majority of the C6-C9 branched-chain alkanes are found in the 145°
to 220°F and the 220° to 280°F fractions, the finding that these two fractions
were highly toxic agreed well with the results for individual chemicals. The
high degree of toxicity of the light alkylate naphtha was also in good agreement
3-26
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TABLE 3-21. EFFECTS OF 4 WEEKS' ORAL EXPOSURE
TO FRACTIONS OF UNLEADED GASOLINE
Test material
Dose
(g/kg/day»
5 days/week)
Average
nephropathy
score
Saline
PS-6 unleaded gasoline
Light catalytic-cracked naphtha
Heavy catalytic-cracked naphtha
Light catalytic-reformed naphtha
Light alkylate naphtha
145-220°F gasoline fraction
220-280°F gasoline fraction
280-end°F gasoline fraction
0.5
2.0
0.5
2.0
0.5
2.0
0.5
2.0
0.5
2.0
0.5
2.0
0.5
2.0
0.5
2.0
27
84a
833
37a
53a
36a
34a
33
38a
96a
88a
60a
89a
99a
104a
42a
31
ap £ 0.05, Mann-Whitney U test,
3-27
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TABLE 3-22. EFFECTS OF 4 WEEKS' ORAL EXPOSURE
TO ORGANIC CHEMICALS PRESENT IN GASOLINE
(SERIES 1)
Test material
Saline
PS-6 unleaded gasoline
n-Pentane
2-Methyl butane
2-Hethyl pentane
2 »3-Di methyl butane
2,2,5-Trimethylhexane
2-Methyl -2-pentene
Methyl cycl opentane
m-Xylene
Dose
(g/kg/day,
5 days /week)
—
0.5
2.0
0.5
2.0
0.5
2.0
0.5
2.0
0.5
2.0
0.5
2.0
0.5
2.0
0.5
2.0
0.5
2.0
Average
nephropathy
score
30
92a
91a
27
23
25
21
46a
59a
76a
6ia
943
96a
30
35
29
34
27
26
ap < 0.05, Mann-Whitney U test,
3-28
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TABLE 3-23. EFFECTS OF 4 WEEKS' ORAL EXPOSURE
TO ORGANIC CHEMICALS PRESENT IN GASOLINE
(SERIES 2}
Test material
Saline
PS-6 unleaded gasoline
n-Hexane
2-Methyl hexane
2 , 3-Di methyl pentane
2,2,4-Trimethylpentane
Trans -2-peritene
To! uene
1 ,2 ,4-Trimethy 1 benzene
Dose
(g/kg/day,
5 days/week)
—
0.5
2.0
0.5
2.0
0.5
2.0
.0.5
2.0
0.5
2.0
0.5
2.0
0.5
2.0
0.5
2.0
Average
nephropathy
score
29
64a
55a
27
31
42a
36
61a
66a
76a
85a
27
29
34
19
33
31
ap _< 0.05, Mann-Whitney U test,
3-29
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with results fop individual chemicals since 45% of an analyzed sample was found
to consist of trimethyl pentane,
3.4.4. 4-Week Oral Nephrotoxicity Screening Study in Male F344 Rats (Tegeris
Laboratories, 1985)
This study was designed to evaluate the nephrotoxicity of a variety of
aliphatic hydrocarbons present in the 28Q°F+ distillate fraction of unleaded
gasoline. The following chemicals were tested:
API PS-6-fuel 2,2,7,7-Tetramethyloctane
2,3-Dimethyl octane 2,2,4,4-Tetrarnethyloctane
2-Methyldecane 2,3,3-Trimethyldecane
Decane 2,2,4,4-Tetramethyldeeane
3-Methyloctane 2,3-Di methy1decane
Octane 2,2,4,4,5,5,7,7-Octamethyloctane
2,2,3-trimethyl octane
Fischer 344 male rats were exposed to the test materials via oral gavage,
5 days/week for 4 weeks. Total dosage was 2.0 g/kg body weight. Only three
of the individual chemicals induced detectable toxic effects in the kidney. In
comparison with the API PS-6 fuel, which was given a moderately severe rating
for induction of nephropathy, 2,2,4,4-tetramethyloctane was rated as severe;
2,2,3-trimethyloctane as moderate; and 2,2,4,4-tetramethyldecane was rated as
inducing only slight effects.
3.5. RENAL EFFECTS OF DECALIN IN SEVERAL LABORATORY MAMMALIAN SPECIES (ALDEN
ET AL., 1983)
A comparison of the renal effects in various laboratory mammalian species
exposed to decalin (a prototype volatile hydrocarbon composed of two cyclo-
hexane rings) was discussed by Alden et al. (1983). One of the observations
presented was that a 91-day inhalation exposure to 5 ppm and 50 ppm decalin
induced renal toxicity in male Fischer 344 rats and not in females, male or
female mice, male or female dogs, and male or female guinea pigs (Table 3-24).
3-30
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TABLE 3-24. BIOLOGICAL TESTING OF DECALIN,
A PROTOTYPE VOLATILE HYDROCARBON
Species tested Renal injury Reference
Rats (male/female) +/- AFAMRL-TR-79-121
(Wright-Patterson AFB)
Mice (female)
Dogs (male/female) -/-
Guinea pigs (male/female) -/- AFMRL-TR-78-55
(Wright-Patterson AFB)
Mice (male) - Dr. Logan Stone
(personal communication)
The observed renal effects in male rats included hyalin droplets in the cyto-
plasm of proximal convoluted tubular epithelial cells, granular casts at the
junction of the inner and outer band of the outer zone of the medulla, and
augmented chronic glomerulonephropathy. These droplets consist of an alpha-2-
microglobulin, a protein synthesized in the male rat liver under the control
of testosterone and endogenous corticosterone. They occur spontaneously in
sexually mature male rats but not in castrated males, in female rats, or in
humans.
3-31
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3.6. TOXICITY OF SYNTHETIC FUELS AND MIXED DISTILLATES IN LABORATORY ANIMALS
(MacNAUSHTON AND UDDIN, 1983)
Toxlcity studies on mixed distillates and synthetic fuels In experimental
animals have been or are being done by the United States Air Force, and prelim-
inary results of these studies were reported by MacNaughton and Uddin (1983).
The studies are summarized below. The design of the experiments, in which the
agents were given by inhalation, is shown in Table 3-25. Beagle dogs, Fischer
344 rats, Syrian Golden hamsters, and C57BL/6 mice were used.
3.6.1. Studies with RJ-5 Synthetic Fuel
RO-5 fuel consists of hydrogenated dimers of norbornadiene with a vapor
pressure of 1.3 kPa at 103°C.
Results of the studies with a 1-year exposure to 30 mg/m^ and 150 mg/m^
were as follows;
1. Decreased body weight gain in rats and dogs, with possible appetite sup-
pression.
2. Acute lung Inflammation and some bronchopneumonia in rats and dogs sacri-
ficed immediately after 6 months of treatment.
3. After a 1-year holding period, there was a 25% incidence of alveolar car-
cinomas in CF-1 mice (the strain shown in the workshop proceedings), a
strain predisposed to this tumor type.
The results of the studies 1n which dogs, mice, hamsters, and rats were ex-
posed to 30 or 150 mg/m^ for 1 year followed by a 1-year holding period were as
fol1ows:
1. Decreased body weight gain in exposed male rats and male hamsters through-
out the study. Increased body weight gain in exposed female rats during
treatment was reversed during the post-treatment period.
2. Decreased (p < 0.05) kidney/body weights in exposed female rats.
3-32
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TABLE.3-25. DESCRIPTION. OF FUEL INHALATION EXPOSURES
Fuel
Exposure
(months)
Concentration
(mg/m3)
Species3 End date
Synthetic
JP-10
RJ-5
RJ-5
Mixed distillate
12, intb
6, contc
12, int
560
155
30, 150
D,R,M/F,H
D,R,M/F,M
D,R,M/F,H
aD (dogs); R (rats); M (monkeys); M/F (mice, female); H (hamsters).
^Intermittent (6 hours/day, excluding weekends and holidays).
cContinuous.
^Shale.
Completed
Completed
Completed
JP-4
JP-4
JP-4
JP-5
JP-5 (S)d
JP-7
JP-8
JP-TS
DFM
DFM (S)
8, int
3, cont
12, int
3, cont
3, cont
12, int
3, cont
12, int
3, cont
3, cont
2,500, 5,000
500, 1,000
500, 1,000
150 750
250, 750
150, 750
500, 1,000
200, 1,000
50, 300
50, 300
D,R,M,M/F
D,R,M/F
R,M/F
D,R,M/F
D,R,M/F
R,M/F
R,M/F ,
R,M/F
R.M/F
R,M/F
Completed
Dec. 1983
Jul. 1984
Compl eted
Completed
Dec. 1985
Jul. 1985
Dec. 1985
Completed
Compl eted
3-33
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3. Four (7%) renal cell adenomas and five (8%) renal cell carcinomas in high-
dose male rats; one (2%) renal cell carcinoma in a low-dose male rat. No
renal cell carcinomas were seen in controls.
4. Other kidney lesions in exposed male rats were:
Incidence
Lesion 150 mg/m3
Renal medullary 57/62 (92%)
mineralization
Moderate pelvic 58%
urothelial hyperplasia
Hyaline droplets 18%
Cortical cysts 24%
30 mg/m3 Control
2/59 (3%) 0%
7% 2%
19% 2%
2% 0%
3.6.2. Studies with JP-10 Synthetic Fuel
JP-10 fuel is a bicyclic, bridged compound; exotetrahydrodi(cyclopenta-
diene), with a vapor pressure of 1.87 kPa.
Results of the studies with a 1-year exposure at 562 mg/m3 followed by a
1-year recovery period were:
1. Slight weight loss in exposed rats and hamsters.
2. Hepatocellular vacuolization in 50% of the control and 75% of the exposed
female mice.
3. Nine renal cell carcinomas in treated male rats compared to one in contols;
poorly differentiated malignant neoplasms in one control and one treated
male rat.
4. Other renal effects in male rats were:
3-34
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Incidence
Lesion
Treated
Control
Augmented renal
tubule degeneration
compatible with old-
rat nephropathy
Medullary mineral deposits
(mineralized cell debris)
Papillary hyperplasia of
renal pelvic epithelium
43/49 (87%)
100%
26/49 (53%)
32/49 (65%)
0%
2/49 (4%)
5. No toxic lesions in female mice.
6. Adrenal cortical adenomas and carcinomas were found in 27% of the control
and 28% of the treated male hamsters; however, adrenal zona glomerulosa
adenomas and adrenal zona glomerulosa hyperplasia were found in 14% and
72% of treated male hamsters, respectively, and 5% and 45% of control male
hamsters, respectively.
3.6.3. Studies with JP-4 Mixed Distillate
JP-4 mixed distillate has characteristics similar to gasoline and has a
vapor pressure of 13 kPa. JP-4 represents 85% of the turbine fuel used by the
Department of Defense.
Results of studies with an 8-month intermittent exposure to 2,500 and 5,000
mg/m3 (containing 80 mg/m3 benzene) were:
1. Increased organ and organ/body weights for kidney, liver, spleen, and lung
in exposed male rats.
2. A 27% incidence of bronchitis in exposed rats.
3. A transient increase in red blood cell fragility in female dogs.
3-35
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Results of studies with a 90-day continuous exposure to 500 and 1,000 mg/
m3 with a 19-month holding period were:
1. Increases in serum globulin and total protein and BUN in low-dose and high-
dose dogs.
2. Decreased body weight gain in exposed male and female rats during treatment.
3, Centrilobular hepatocellular fatty change in 88% of the low-dose and 89% of
the high-dose female mice.
4. Kidneys of all exposed male rats contained hyalin droplets in the proximal
tubular epithelium, and focal dilatation of renal tubules near the cortico-
medullary junction with plugging by cellular debris was found in 96% of the
low-dose and 100% of the high-dose male rats.
Results of studies with a 1-year exposure to 500 and 1000 mg/m3 were:
1. Decreases in body weight and in kidney and liver weights in high- and low-
dose male rats.
2. Decreases in spleen and kidney weights in low-dose female rats.
3.6.4. Studies with JP-5
JP-5 mixed distillate is the other major turbine engine fuel besides JP-4.
Results of studies with a 90-day continuous exposure of dogs, rats, and mice to
150 and 750 rng/m^ and a 19-month post-exposure period were:
1. Decreased body weight in exposed male rats.
2. Increased BUN and serum creatinine in male and female high-dose rats.
3. Mild, diffuse fatty change with small vacuoles in hepatocytes of 3% of
the control, 73% of the low-dose, and 24% of the high-dose mice.
"Foamy" hepatocellular cytoplasmlc vacuoles were found in 18% of the con-
trol, 15% of the low-dose, and 44% of the high-dose female mice.
4» Male rats sacrificed at the end of the 90-day exposure period had dilated
renal tubules filled with granular necrotic debris at the corticomedullary
3-36
-------
junction.
5. By 19 months post-treatment, old-rat nephropathy was evident in 96%, 96%,
and 84% of the high-dose, low-dose, and control males, respectively. Old-
rat nephropathy was more severe in treated males. Renal medullary tubular
mineralization was found in 82% of the high-dose, 59% of the low-dose, and
none of the control male rats. A dose-related focal hyperplasia of the
renal pelvis was reported.
In summary, chronic exposure to RJ-5 and JP-10 synthetic fuels induces a
common pattern of nephrotoxicity leading to renal carcinomas. Similar studies
with JP-4 and JP-5 show the same preneoplastic lesions, but no information is
I
available about neoplastic response.
3.7. INFLUENCE OF BENZENE ON THE RENAL CARCINOGENIC EFFECTS OF UNLEADED GASO-
LINE VAPOR IN MALE RATS
The quantitative estimate of risk from exposure to benzene has recently
been updated in an interim report (U.S. EPA, 1985). Although a number of ani-
mal studies, carried out by the appropriate route of exposure (inhalation),
have shown that benzene is carcinogenic in several organs, the risk estimates
derived from these studies were considered to be less reliable than epidemio-
logic data for estimating risk to humans. The unit risk due to a lifetime
exposure to 1 ppm benzene in the air was therefore estimated from leukemia
incidence data in exposed humans. Using various models and a combination of
assumptions and epidemiologic studies, 21 unit risk estimates ranging from
0.9 x 10-2 to 1 x 10-1 were obtained. Based upon the criteria of using the
data from all epidemiologic studies with reasonable exposure information and
an average value over all mathematical models thought to be plausible, a com-
bined unit risk estimate of 2.6 x 10-2 was derived. This was taken to be the
CAG's best judgment of unit risk.
3-37
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3.8. CONCLUSIONS OF THE UAREP REPORT (1983) ON TOXICOLOGICAL INTERPRETATION OF
HYDROCARBON-INDUCED KIDNEY LESIONS
An analysis of the toxicology and carcinogenicity of unleaded gasoline and
other hydrocarbons, issued by the Universities Associated for Research and
Education in Pathology, Inc. (UAREP) was published in December, 1983. This
section summarizes the review and interpretation of the data presented in that
document.
3.8.1. Assessment of the API Chronic Inhalation Study with Unleaded Gasoline
Vapor in Rats and Mice
1. There were significant increases in renal adenoma and carcinoma inci-
dence in male Fischer 344 rats and in hepatocellular adenoma and carci-
noma incidence in female B6C3F1 mice exposed to an aerosol of whole
unleaded gasoline vapor. The bioassay was well designed and conducted,
and there were several independent examinations of the kidney slides.
2. Male Rat Kidney Lesions in Exposed Groups
a. Three-month findings: Focal degeneration in the proximal tubules,
hyaline droplets in the proximal tubules, granular casts at the
junction between the inner and outer stripes of the outer medulla,
some evidence of regeneration. The lesions seemed dose related,
with the greatest prominence in the high-dose group.
b. Findings by 12 months: Karyomegaly, probably in the P% segment of
the proximal tubules. Old-rat nephropathy, in treated as well as
control rats, shown as atrophy of the PI segment of the proximal
tubule with basement membrane thickening, mesangial thickening in
the glonieruli, interstitial fibrosis with chronic inflammation, and
periodic acid-Schiff (PAS)-positive tubular colloid casts in the
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distal nephron. Calcium hydroxyapatlte deposition in the papilla
was evident 1n the exposed groups.
c. Findings after 12 months: Areas of hyperplasia. Progression of
the severity of old-rat nephropathy, which was greater in the
treated groups than in controls, as well as preneoplastic and neo-
plastic lesions.
d. Findings at 18 months: Renal adenoma in one rat.
e. Findings at 24 months (final sacrifice): Renal adenomas and car-
cinomas in treated rats.
3. Liver Pathology in Female Mice
No treatment-related lesions were found between 3 and 18 months.
It could not be determined whether preneoplastic lesions preceded the
liver tumors. Acute effects, such as fatty metamorphosis from exposure
of mice to other hydrocarbons, were neither reported nor looked for in
the carcinogenicity study with unleaded gasoline.
3.8.2. Interpretation of the Toxicologlcal Carcinogenic Findings in theCar-
cinogenicity Study with Unleaded Gasoljne byUAREP
1. Male Rat Kidney - Nonneoplastic Lesions
Signs of acute and chronic renal toxicity were evident. There was
some necrosis, but more often there was cell degeneration and/or bleb-
bing with release of cell debris forming casts between the pars recta
(P3 segment) and the thin limb. The kidney lesions in exposed male
rats were unique in that they were unlike those induced by known
nephrotoxins such as mercuric chloride, halogenated hydrocarbons, or
nitrilotriacetic acid.
The mechanism of gasoline-induced nephrotoxicity is obscure.
There was no uniform necrosis in the ?3 segment, and many lesions were
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found in the Pj_ and P£ segments. It 1s currently not possible to
accurately characterize the nature and location of the toxic lesions
1n male rat kidneys in this study.
The toxic kidney lesions were clearly distinguishable from old-rat
nephropathy, which in the latter involved the whole kidney and showed
atrophy of the PI segment of the proximal tubule and glomerular sclero-
sis. However, exposure to unleaded gasoline vapor augmented the sever-
ity of old-rat nephropathy.
The most striking chronic nonneoplastic lesion in exposed rats was
severe mineralization of the tubules in the papilla. The deposits were
characterized as calcium hydroxyapatite. The etiology behind the miner-
alization is uncertain, but it was hypothesized that chronic damage in
the proximal tubule and higher segments in the nephron leads to phos-
pholipid vesicle-induced calcification. The observed calcification pat-
tern is unique to hydrocarbon exposures, and chronic exposure of male
rats to JP-10 synthetic missile fuel has also induced mineralization in
the kidney.
2. Male Rat Kidney - Preneoplastic and Neoplastic Lesions
The neoplastic process resulting from treatment of male rats with
unleaded gasoline resembles that induced by several other renal car-
cinogens: karyomegaly, probably in the ?3 segment, followed by hyper-
plasia, followed by adenomas that were often cystic, and carcinomas.
These preneoplastic and neoplastic lesions were found in association
with the increased severity of old-rat nephropathy, but it was not pos-
sible to characterize their precise location, nature, or progression.
It was not possible to establish the influence of old-rat nephropathy
on these lesions, and the mechanism for the induction of these preneo-
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plastic and neoplastic lesions is unknown.
3. Liver Lesions in Female Mice
Acute toxicity or preneoplastic lesions were not found in the
livers of female mice, according to the carcinogenicity study report;
however, hematoxvlin and eosin staining is not sensitive for the detec-
tion of preneoplastic lesions. Acute toxicity studies with other
hydrocarbons in mice have revealed fatty metamorphosis in the liver.
The neoplasms in livers of female mice exposed to unleaded gasoline
vapor resembled mouse liver neoplasms found in other studies, but such
neoplasms are often phenotypically similar regardless of etiology.
3.8.3. Review of Human Kidney Lesions
1. Acute - There are no thorough studies on human kidney lesions resulting
from acute exposure to hydrocarbons. Case reports indicating structural
and functional changes in the kidney show the main lesions as variants
of an immune complex type of glomerular nephritis, a type of lesion that
has not been found in rodents. The mechanism of acute toxicity in the
case reports is difficult to pinpoint because of confounding factors.
2. Chronic - There is no persuasive evidence that human exposure to gaso-
line is associated with renal cancer. There is no evidence for the
calcification of papilla or calculi in the bladder or kidney from human
exposure to gasoline. Human renal adenocarcinomas are morphologically
similar to those found in male rats chronically exposed to unleaded
gasoline vapor, as well as to well-characterized models of rodent renal
neoplasia induced by chemical carcinogens. However, renal adenocarcin-
omas develop in human kidneys that are normal except for a putative
increase in hyperplasia and adenomas, whereas adenocarcinomas in the
kidneys of rats chronically exposed to unleaded gasoline vapor occurred
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with a background of chronic, and often severe, renal disease. An
apparent Increase in the incidence of adenomas and carcinomas in the
kidneys of dialysis patients is the only possible equivalent to adeno-
carcinoma induction in rats. This possible similarity between humans
and rats needs to be further investigated, but it is consistent with
the view that any type of chronic renal injury, e.g., old-rat nephro-
pathy, can possibly act as a promoter and/or cocarcinogen in the induc-
tion of renal neoplasia.
Human renal cancer can occur along with chronic interstitial
nephritis, e.g., chronic analgesic nephropathy. This type of cancer
arises in the renal pelvic epithelium to yield transitional cell car-,
cinomas totally different in location and structure from the lesions
seen in the chronic rat study with unleaded gasoline.
3.8.4. Species and Sex Comparison ofthe Kidney
Renal morphology has been most thoroughly studied in the rat, rabbit, and
dog. There has been no detailed ultrastructural study in the mouse kidney. A
detailed ultrastructural study has been done with renal biopsies from 10 human
males who were screened for renal dysfunction.
The human kidney is multilobular, without the distinct zonation caused by
the alignment of nephrons in the unilobar rodent kidney. The rodent kidney
has a long loop of Henle and long papillae to allow extensive concentration of
urine. The human kidney has nothing like the outer stripe of the outer medulla
i
in the rodent kidney, which contains the pars recta (?3 segment) of the proxi-
mal tubule and the ascending limb of the loop of Henle. The human kidney has
an ultrastructurally simple proximal tubule in contrast to the kidney of the
rat, mouse, and rabbit. No morphological differences between the kidneys of
male and female humans have been described.
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The size and number of lysosomes in the Pj, ?2» and P3 segments in the
male rat kidney are larger than in the female rat kidney. This may be corre-
lated with the unique production of alpha-2-microglobulin and resorption of
this protein in the proximal tubule in the male rat kidney. Endoplasmic re-
ticulum and microbodies are more prominent in female than in male rat kidneys,
which may indicate a difference between them in metabolic capacity. Castra-
tion and hypophysectomy of male rats decrease the differences in the proximal
tubule, particularly lysosomes, between male and female rat kidneys.
Hyaline droplets in the PI and P£ segments have been found in kidneys of
male rats exposed to hydrocarbons other than unleaded gasoline vapor, e.g.,
decalin. These droplets consist mainly of protein, including alpha 2-micro-
globulin, within the phagolysosomal system of the male rat kidney. In the male
rat kidney it is presumed that, with no evidence of acute glomerular lesions,
these droplets represent accumulations of endogenous proteins that are produced
in the male rat liver and resorbed by the kidney, to be phagocytized by lyso-
somes. Protein accumulation by the kidney could be due to increased synthesis
and uptake and/or decreased degradation. The mechanism of hydrocarbon nephro-
toxicity is presently unclear. Exposure to decalin produces hyaline droplets in
male but not in female rats, and these droplets have been observed to disappear
quickly after cessation of treatment with decalin. However, it is not known
whether chronic lysosomal overload can produce cell injury in rat kidney prox-
imal tubules.
Less is known about renal mixed function oxidase (MFO) than about liver
MFO. There are marked species, strain, and sex differences in the metabolic
capability of the rodent kidney. There are potentially significant quantita-
tive and, to a lesser degree, qualitative differences in renal, MFO components
and activity among species. In all species studied thus far, MFO activity has
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been localized in the proximal tubule and usually in the ?3 and/or Pg segments.
Little data exist on MFO in the human kidney. Metabolites from other organs
can possibly go to the kidney to produce toxicity in vivo. Specific studies on
renal MFO and unleaded gasoline toxicity are lacking, but there is some evidence
that renal MFO may play a role in the renal toxicity of other hydrocarbons.
3.8.5. Rodent Kidneys and Other Hydrocarbons
The only hydrocarbon fuel other than unleaded gasoline that has been test-
ed in a chronic rodent bioassay is the synthetic missile fuel JP-10. Exposure
to JP-10 was found to induce renal carcinomas in male Fischer 344 rats.
Most solvents and hydrocarbons have induced similar acutely toxic lesions
in the rodent kidney; however, no specific mechanism of action has been deter-
mined, nor has an ultrastructural analysis been done.
Paraffin and isoparaffin fractions have been found to be more acutely
toxic in rodent kidneys than are other fractions of petroleum products. The
most toxic individual compounds were C6-C9 aliphatics with multiple branch-
ing.
The mutagenicity of unleaded gasoline has been reported as negative. How-
ever, in the in vitro assays, only S-9 fractions from rat liver were used,
which may not relate to other organs: also, there may have been a problem with
the volatility and solubility of the gasoline in these assays.
None of the tested hydrocarbons has produced a uniform necrosis in the
pars recta epithelium, as is commonly seen in the rodent kidney with other
renal toxins, such as mercuric chloride.
Acute lesions in the rodent kidney from hydrocarbon exposure have been
characterized as hyalin droplet accumulations, focal areas of degeneration and
necrosis, epithelial regeneration, and granular casts in the corticomedullary
junction.
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3.8.6. Old-Rat Nephropathy
Old-rat nephropathy is characterized by interstitial fibrosis, thickening
of tubular basement membranes, interstitial chronic inflammation, vascular
thickening in interlobular and afferent arterioles, glomerular hyalinization,
and tubular atrophy, especially 1n the PI segment of the p'roximal tubule.
In the unleaded gasoline cardnogenicity bioassay, increased numbers of
mitoses, hyperplasia, karyomegaly, and other preneoplastic lesions were not
seen in control rats.
Old-rat nephropathy may start at an early age. Old females show a lesser
degree of nephropathy than males. The severity of old-rat nephropathy varies
among strains.
Old-rat nephropathy was morphologically different from preneoplastic
lesions in the API carcinogenicity study of unleaded gasoline vapor. However,
a possible etiologic relationship between old-rat nephropathy and toxic lesions
from exposure to unleaded gasoline vapor cannot be ruled out.
In humans, chronic renal disease has been associated with renal adenocar-
cinoma only in kidney dialysis patients. Lesions in the kidneys of these
patients are morphologically similar to those seen in male rats in the chronic
unleaded gasoline vapor study, as well as in other rodent studies with hydro-
carbons. No human control group has been studied along with the dialysis
patients.
Old-rat nephropathy resembles focal and segmental glomerulosclerosis in
human disease and, to a lesser extent, arteriolar and arterial nephrosclerosis
in aging humans. Several patients with renal-carcinoma following dialysis had
renal failure secondary to nephrosclerosis, and one of these patients had mul-
tiple calculi in the kidney.
Studies with the liver indicate a greater ability of younger than of older
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rats to metabolize carcinogens; however, a similar comparison with the kidney
still needs to be explored.
3.8.7. Comparative Nephrotoxicity andNephrocarcinogeniclty
Species, strain, and sex differences in response to nephrotoxins are clear-
ly evident. Many chemical classes of nephrotoxins induce similar morphological
effects, and most nephrotoxic chlorinated hydrocarbons affect primarily the ?3
segment of the proximal tubule, which is apparently lacking in humans. However,
few agents have well-characterized mechanisms of acute and chronic renal toxi-
dty. Some chlorinated hydrocarbons, e.g., chloroform, have chronic, carcino-
genic effects that do not always correspond to acute effects in terms of target
organ response.
Chloroform induces a selective and uniform degeneration and necrosis of
proximal tubule epithelial cells, with the effect being greatest in areas with
the greatest MFO activity, as supported by studies in rats and dogs. Similar
patterns of proximal tubule degeneration from exposure to chloroform have been
observed in these two species.
There is evidence that similarity of morphological end points does not
necessarily indicate similarity between mechanisms. For example, nitrilo-
acetic acid may act as a promoter in the induction of renal adenocarcinomas in
rats, but the renal adenocarcinomas induced by this agent are morphologically
similar to those observed in rats in the chronic unleaded gasoline vapor study.
Acute, but not chronic, renal lesions from mercuric chloride treatment are
unlike those induced by exposure to hydrocarbons. Mercuric chloride, as well
as chlorinated hydrocarbons, initially induces selected necrosis in the renal
?3 segment, and with higher doses also induces progressive necrosis in the ?i
and ?2 segments.
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3.8.8. Significance to Humans of the Chronic Inhalation Study with Unleaded
Gasoline Vapor in Rats and Mice
1. The relationship between old-rat nephropathy and renal neoplasia, in the
chronic unleaded gasoline study is presently uncertain. Although renal
neoplasia in male rats exposed to unleaded gasoline does not appear to stem
from basophilic cells in the old-age renal lesions, a role of the old-age
lesions in the etiology of renal neoplasia presently cannot be ruled out.
In humans, chronic renal disease has been associated with an increased
incidence of renal cancer.
2. No statistically significant association between renal epithelial neoplasia
and environmental agents, except for cigarette smoke, has been found in
humans. Tumors of the renal pelvis in humans have been associated with
exposure to environmental agents.
3. Anatomical and physiological differences between rat and human kidneys may
contribute to differences in renal responses to environmental agents,
including unleaded gasoline. This issue needs further study.
3.9. RESEARCH IN PROGRESS OR PLANNED UNDER THE SPONSORSHIP OF THE AMERICAN
PETROLEUM INSTITUTE
The purpose of the research sponsored by the API and being carried out
principally by the Chemical Industry Institute for Technology (CUT) is to
attempt to link kidney pathology in male rats induced by gasoline vapors to the
induction of cancer, and to show that this is a unique response in the male
rat. According to these investigators' hypothesis, tumors of the kidney arise
because of an increased rate of errors in the replication of DNA in the kidney
cells. This increased replication error rate accompanies hyperplasia in the
kidney tissue, which is a response to cellular damage caused by accumulation in
the kidney proximal tubule cells of a low molecular weight protein (alpha-2-mi-
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croglobulin) complexed with a metabolic product of the branehed-chain aliphatic
hydrocarbons present in gasoline vapors. After complexing with the hydrocar-
bons, the protein becomes resistant to breakdown by the tubule cells, resulting
in accumulation of hyaline droplets, followed by cell death, the accumulation
of cellular debris, and an increased rate of cell division.
In support of this hypothesis, it was shown that only male rats and not
female rats, mice, hamsters, or humans produce alpha-2-microglobulin in large
amounts, that radioactively-labeled hydrocarbons administered to male rats
appear in kidney tissue complexed with proteins at the place where tumors arise
(unpublished data), and that DNA repair, an indicator of genotoxicity, is
absent in kidney cells following exposure to unleaded gasoline (Loury and ,
Butterworth, 1986). Studies will be carried out to determine if gasoline acts
as an initiator, as a promoter, or as a complete carcinogen. Finally, attempts
are being made to develop an immunoassay for detection of proteins analogous to
alpha-2-microglobulin in humans.
3,10. SUMMARY OF ANIMAL STUDIES
A lifetime inhalation bioassay of unleaded gasoline in Fischer 344 rats and
B6C3F1 mice induced a significant increase in renal carcinomas in the kidney
cortex of male rats and a larger, also significant increase in hepatocellular
carcinomas in female mice. Female rats and male mice had no significant treat-
ment-related induction of tumors at any organ site. The incidence of renal
carcinomas was significantly increased only at the highest dose tested (2,056
ppm). However, if renal adenomas, carcinomas, and sarcomas are combined, the
increase was significant at both the high and intermediate dose levels. In
mice the increase in the incidence of liver carcinomas alone and adenoma and car-
cinoma combined was statistically significant only in the highest dose group.
Moderate decrements in body weight gain in the high-dose groups indicate that
'X
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the maximum tolerated dose was reached. Glomerulonephrosis occurred in nearly
all male rats, and mineralization of the pelvis was correlated with dose.
However, there was no correlation between animals with tumors and those with
mineralization.
The acute and subchronic renal toxicity of decalin, a volatile hydrocarbon
of the same general type as those contained in gasoline, is confined to male
rats and does not occur in female rats or in mice, dogs, or guinea pigs. In
a series of 21-day inhalation exposures of male rats to a variety of chemical
fractions of gasoline, renal toxicity was correlated with the paraffin compo-
nents; specifically, those having C6-C9 carbons with one or more branches, and
not with the aromatic compounds in the mixture. The same pattern of renal
toxicity as well as a positive renal tumor response occurs in response to
chronic inhalation of two synthetic fuels (RJ-5 and JP-10). Chronic inhalation
studies with the jet fuels used by the Air Force and Navy (JP-4 and JP-5) have
shown the same nephrotoxic lesions, but information on the carcinoma response
is not available. The renal toxicity pattern observed with exposure to hydro-
carbon mixtures, involving protein accumulation in renal tubules, is clearly
different than the kidney lesions occurring spontaneously in old rats, and
occurs in males of both Fischer 344 and Spraque-Dawley strains, but not in
females of these strains or in mice or monkeys.
Mutagenesis tests of unleaded gasoline have been carried out in Salmonel-
la, yeast, mouse lymphoma in vivo cytogenetics, and mouse dominant lethal
systems. Various gasoline feedstocks have been tested in mouse lymphoma and
in vivo cytogenetics assays. The results of most of these assays have not met
the criteria for positive responses, A detailed examination of their adequacy
is in process.
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4. EPIDEMIOLOGIC STUDIES
The purpose of this section is to review the epidemiologic literature
to determine if there is any epidemiologic evidence for an association between
gasoline exposure and cancer risk.. Since unleaded gasoline was only introduced
in the mid-1970s, even recent epidemiologic studies are not likely to show an
unleaded gasoline effect because of the long latency period generally associa-
ted with cancer. Therefore, this discussion is not limited to unleaded gasoline
exposure but rather addresses any potential gasoline exposure.
Reviewed here are seven epidemiologic studies—six case-control studies
and one proportionate mortality study—that evaluated the association between
cancer risk and employment in the gasoline service industry, and 44 studies
that assessed the association of cancer risk and employment in the petroleum
industry, 25 of which were refinery-based. Four epidemiologic studies that are
currently in progress are also reviewed. Ecological studies that evaluated the
association of the petroleum industry and excess cancer risk are not reviewed
(Blot and Fraumeni, 1976; Blot et al., 1977; Hearey et al., 1980; Henderson
et al., 1975; Menk and Henderson, 1976; Blattner et al., 1981; Austin et al.,
1984; Kaldor et al., 1984). Also excluded are early investigations of petroleum
refinery workers (Gafafer, 1940; Wade, 1963; Baird, 1967); the use of non-age-
adjusted mortality rates in these early studies makes any interpretation of
their results questionable. Also not included are studies designed to assess
specific petroleum refinery exposures of substances other than gasoline, e.g.,
benzene, lubricating-dewaxing (Hendricks et al., 1959; Rushton and Alderson,
1981b; Sherwood, 1972; Thorpe, 1974; Tabershaw Occupational Medicine Associates,
1980; Tsai et al., 1983; Wen et al., 1985); and studies of petrochemical work-
ers (Alderson and Rattan, 1980; Alexander et al., 1982; Austin and Schnatter,
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1983; Nicholson et al., 1982; Waxweiler et al., 1983a). Review articles are
also not included; however, specific conclusions by the authors of reviews may
be included (Savitz and Moure, 1984; Enterline and Viren, 1984; Raabe, 1984;
Higginson et al., 1984; Bingham et al., 1980; Leese, 1982; Joyner, 1982;
Weaver, 1982).
4.1. EPIDEMIOLOGIC STUDIES OF WORKERS IN THE GASOLINE SERVICE INDUSTRY
4.1.1. Stemhagen et al. (1983)
This is a retrospective case-control study of liver cancer. Cases were
any New Jersey resident diagnosed with primary liver cancer between January 1,
1975, and March 1, 1980. Those diagnosed between January 1, 1975, and Septem-
ber 30, 1978, were identified through record searches of all New Jersey hospi-
tals. Cases diagnosed after September 1978 were identified through the new
statewide Cancer Registry. To ensure that all cases were ascertained, a search
of all death certificates for the period 1975-79 was also conducted. Those
with primary liver cancer (International Classification of Diseases [ICD] 155.0
and 155.1) as the underlying cause of death were traced to the hospital where
the death occurred. After verifying that the initial diagnoses were made
during the study period, these deceased persons were added to the study popu-
lation.
A single physician reviewed medical records for all the cases to verify
that cases were histologically confirmed primary liver cancers. Diagnoses were
considered established if the pathologist had unequivocally diagnosed the
tumors as primary malignant tumors of the liver. A consultant pathologist
reviewed the medical records and/or examined histologic sections to decide
doubtful cases.
Controls, two per case, were individually matched to the cases on the
basis of age (+2 years), sex, race, and county of residence. Living controls
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were matched to living cases, and deceased controls were matched to deceased
cases. Living controls were selected from patient records in the hospital in
which the case was diagnosed, provided that the potential control met the
matching criteria and had the closest admission date to that of the case.
Deceased controls were selected from state death certificate files. For de-
ceased cases, the two controls that met the matching criteria and had the
closest date of death to the case were selected. Excluded from the control
population were potential controls with a known diagnosis (known either through
medical or death certificate records) of liver cancer, hepatitis, cirrhosis,
or other liver diseases. Also excluded as potential controls were deceased
persons with homicide or suicide listed as the cause of death.
Of 959 cases of supposed primary liver cancer identified, 624 (66%) did
not meet the criteria for studv inclusion. Of these, 385 (40%) were excluded
because the histologic evaluation indicated a disease other than primary liver
cancer (e.g., primary site other than liver), and 228 (24%) were excluded be-
cause the diagnosis was not histologically confirmed (e.g., diagnosis based
on liver scan). Of the 335 cases that met the study criteria, medical records
were available for 296; among these, interviews with 901 of either the next-of-
kin respondents or the cases themselves were completed. Of the controls initi-
ally identified, 138 were unavailable (e.g., most moved out of study area). Of
those traced, approximately 77% of either the next-of-kin or the controls
themselves were finally interviewed.
The final study population consisted of 265 cases (178 males and 87
females) and 530 controls (356 males and 174 females); 81.5% of the cases were
diagnosed as hepatocellular carcinoma and 9.1% as cholangiocarcinoma. The most
frequent diagnoses or causes of death for the controls were ischemic heart
disease, lung cancer, or cerebrovascular disease.
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Interviews were conducted in the homes of the living study subjects (4%)
and the proxy respondents (96%). Proxy information on the male cases and con-
trols was usually provided by the wife. Proxy information for the female cases
and controls was usually provided by the sons or daughters of the study subject,
Data were collected on smoking habits, lifetime residence, medical histories,
alcohol consumption, and lifetime occupational histories (since age 12).
Occupational data were coded to the Census Bureau's index of industries and
occupations (U.S. Bureau of the Census, 1970).
The association between liver cancer and specific exposures was deter-
mined by calculating the odds ratio (OR) by the Mantel-Haenszel procedure for
multiple matched controls (Mantel and Haenszel, 1959). Comparisons within
matched triplets were not maintained during the calculation of the adjusted
odds ratio (adjusted for confounding or exposure level). The Mantel (1963)
extension procedure was used to test for dose-response trends.
Results indicated that male primary liver cancer cases were more likely
to be workers in gasoline service stations as compared to controls (OR = 2.88,
9$% confidence interval [CI] 1.20-6.88). When analyses were limited to male
cases with hepatocellular carcinoma and their matched controls, the risk in-
creased more than four times (OR = 4.20, 95% CI 1.55-11.35) that of study
subjects who never worked in gasoline service stations.
Also observed were significant excess risks for male subjects who
worked in laundering, cleaning, and other garment services (OR = 2.50, 95% CI
1.026.14), eating and drinking places (OR = 2.19, 95% CI 1.22-3.92), as well
as bartenders (OR = 2.27, 95% CI 1.03-5.04), winemakers (OR = 3.20, 95% CI
1.11-9.21), those employed in the agricultural industry (OR - 2.08, 95% CI
1.34-3.30), those employed in agricultural production or services exclusive of
horticulture (OR = 2.08, 95% CI 1.33-3.23), and farm laborers (OR = 1.89, 95%
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CI 1.19-3.00) as compared to the controls. The OR for miscellaneous laborers
was significantly deficient (OR = 0.44, 95% CI 0.21-0.94).
A significant dose-response trend for both males (p = 0.0014) and females
(p < 0.012) was found for increasing amounts of alcohol consumption (measured
in milliliters of total ethanol consumed per year). No dose-response was
observed for either males or females for cigarette smoking after controlling
for the effects of alcohol consumption.
The authors indicated that the numbers of males with gasoline service
station exposure were too few to analyze risks while simultaneously controlling
for the effects of alcohol consumption (a significant confounder). However,
since the risk for gasoline service station exposure (OR = 2.88, CI 1.20-6.88)
was greater than the risk for alcohol consumption (OR = 2.52, CI 0.97-6.54) for
those in the medium-heavy category of alcohol consumption, i.e., the category
with the greatest risk, it is possible to infer that not all the excess risk
observed in cases working in gasoline service stations is due to the confound-
ing effects of alcohol.
This study provides limited data to assess the causal association between
gasoline and primary liver cancer in males. Workers in gasoline service sta-
tions, while potentially exposed to gasoline, may be exposed to any number of
potential carcinogens. These have neither been controlled for nor are actual
quantitative measures of gasoline vapor present. No latency analyses were
provided by years of employment in gasoline service. The authors noted that
possible incomplete recall by proxy respondents of alcohol consumption (a sig-
nificant confounder) may have resulted in an underestimation of the risk for
alcohol.
4.1.2. Silverman et al. (1983)
This population-based case-control study was conducted as part of the
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National Bladder Cancer Study (Hoover et al.» 1980). The cases were all per-
sons, ages 21 to 84, with histologically confirmed and newly diagnosed car-
cinoma (or papilloma not specified as benign) of the lower urinary tract
(bladder, renal pelvis, ureter, and urethra), who were diagnosed from December
1, 1977, to November 30, 1978, and were residents of the Detroit metropolitan
area (Macomb, Oakland, and Wayne Counties). The hospitals participating in the
study contributed 97% of the total cases diagnosed in the area. Ninety-five
percent of the cases were diagnosed with urinary bladder cancer, primary site.
Therefore, the term "bladder cancer" was used to mean lower urinary tract car-
cinoma.
For purposes of analysis, the study population was initially limited to
males. Personal interviews were obtained for 81% of the cases. Thirty-one
proxy interviews were conducted because the patients were too ill or had died.
Excluded were 17 cases whose physicians prohibited interviewing; 11 cases that
could not be located; 29 cases that refused to cooperate; and 24 cases for
which proxy respondents were not located, were too ill to be interviewed, or
had died.
The age distribution of the controls was approximately that of the cases,
and the controls were randomly selected from the general population of the
Detroit area depending on age. Controls, ages 21 to 64, were selected by ran-
dom digit dialing of all Detroit area residences with telephones. Those in
the 65- to 84-year age group were randomly selected from Health Care Financing
Administration records for area residents. Of the controls ages 21 to 64, 84%
were interviewed; of the controls ages 65 to 84, 89% were interviewed.
Also excluded from the study was a potential control who had bladder can-
cer before the study period, a case with a histologic type not specified as
transitional or squamous cell carcinoma, and five cases and three controls
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because the subjects never held jobs longer than 6 months or the interview was
considered unreliable. Analyses were finally restricted to white males because
of the small numbers of non-whites. The final study population included 303
white male cases and 296 white male controls.
The questionnaire was designed to obtain detailed information on life-
time occupational history, smoking history, coffee consumption, artificial
sweetener use, residential history, source of water, fluid intake, hair dye
use, and medical history. Occupational data were collected for every job held
for 6 or more months since age 12, and included information on job title and
industry (coded according to the U.S. Bureau of the Census1 alphabetical index
of industries and occupations), years of employment, full-time/part-time sta-
tus, job duties, materials exposed to, and frequency of exposure. Upon comple-
tion of the occupational history, interview subjects were shown checklists of
known and suspected high-risk industries, occupations, and materials to elicit
additional exposure information. The authors did not indicate if the inter-
viewer was "blind" towards the status of the subject being a case or control.
The odds ratio was used to assess the association between occupational
exposures and the incidence of bladder cancer. Stratified analyses were used
to control for the confounding effects of age, smoking, or employment in other
high-risk industries or occupations. The maximum likelihood method was used
to compute summary odds ratios. The authors indicated that relative risk esti-
mates were unaffected by adjustment unless specified. Two-sided 95% confidence
intervals (CIs) for the crude odds ratios were computed by Woolf's (1954)
method; CIs for the adjusted odds ratios were calculated by use of a test-based
interval estimate; however, these were not always presented by the authors.
The Mantel (1963) extension procedure (two-tailed) was used to test for trend.
Risks were estimated relative to the risk for subjects "never employed" in that
4-7
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industry or occupation. Both Industry and occupational exposures were assessed,
Employment experience was defined as "ever employed" as well as by "usual"
occupation or industry. Results were not presented for industries and occupa-
tions in which fewer than 15 subjects worked unless the industry or occupation
had a "special interest because of previous reports,"
Results were presented for 32 categories of industry employment and 54
occupational categories. The vast majority of these occupations or industries
were not associated with the manufacture, marketing, or distribution of gaso-
line; therefore, no discussion of these occupationally related exposures is
presented here.
Three of the industry categories (petroleum extracting and refining,
trucking service, and gasoline service) were considered to have potential gas-
oline exposure. The authors reported an excess risk for "bladder cancer"
cases if they worked in each of these industries. Cases were six times more
likely to be in the categories of "ever employed in the petroleum extracting
and refining industry" as opposed to those "never employed in the industry"
(crude OR = 6.0, 95% CI 0.7-49.8). The risks were elevated for cases (crude
OR = 1,6, 95% CI 0.8-3.5) if they were ever employed in the gasoline service
industry, even after adjusting for the confounding effects of age and smoking
(adjusted OR = 1.3, p value not reported). Cases were more likely to be ever
employed in trucking service (crude OR = 2.2, 95% CI 1.1-4.4) than were con-
trols. Of the 32 industry category comparisons made among those ever employed,
only trucking service was significantly different from unity.
Results were similar whether "usual" industry or "ever employed" in each
industry was considered for those in the gasoline service industry or the
petroleum extraction and refining industry. However, for cases there was a
"twofold increase" in risk for those usually employed in trucking service (OR =
4-8
-------
4.3, p value not reported) 1n comparison to those ever employed in trucking
service (OR = 2.1, p value not reported) after controlling for age and smoking.
Of the 54 occupations specified, truck driver was the only occupation ,in
which cases experienced a significant elevation in risk (crude OR = 2.5, 95% CI
1.4-4,4). After adjusting for age and smoking, risk for cases ever employed as
truckers was still twice (adjusted OR = 2.1 95% CI not reported). Among the
cases who ever worked as garage workers or gas station attendants, risks were
very slightly, although not significantly, elevated to 1.2 (95% CI 0,6-2.4).
Risks were also elevated among those ever employed as taxi cab drivers or
chauffeurs (crude OR = 2.0, 95% CI 0.7-5.4), bus drivers (crude OR = 1.5, CI
0.4-5.3), and delivery men (crude OR = 1.6, 95% CI 0.9-2.6). The age- and
smoking-adjusted odds ratio for delivery men rose from 1.6 for the crude to 1,8
for the adjusted (95% CIs not reported).
Risks were similar when usual occupation was considered in comparison to
ever employed in an occupation. However, the age- and smoking-adjusted odds
ratio for truckers rose from 2.1 for those ever employed to 5.4 for those usu-
ally employed as truckers.
To investigate an excess risk of bladder cancer, a follow-up questionnaire
was administered to 36 of the 42 cases, and to 16 of the 18 controls who had
worked as truckers for at least 6 months. The telephone interview solicited
information on potential exposure to diesel exhausts, type of freight trans-
ported, work-related illnesses, and use of medications to stay awake.
These additional analyses (all adjusted for the effects of age and smok-
ing) revealed that bladder cancer risks were significantly (p = 0.004) associ-
ated with an increasing duration of employment as a truck driver (10+ years
of employment, adjusted OR = 5.5, 95% CI 1.8-17.3). However, no association
between bladder cancer risk and duration of employment as a truck driver prior
4-9
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to 1950 (when diesel trucks became more prevalent) was observed. An elevated
estimate of relative risk for truck drivers who transported petroleum products
was also observed (adjusted OR = 3.6, 95% CI 0.8-16.4). Truckers whose trucks
were usually fueled by others were also at increased risk (adjusted OR = 1.7,
95% CI 0.8-3.9), but not of the same magnitude as those who fueled their own
trucks (adjusted OR = 2.3, 95% CI 0.9-6.1). The authors pointed out that of
the 52 truckers reinterviewed, only 5 cases and no controls drove a diesel
truck while employed as a trucker, and that "most of their diesel exposure
occurred while employed in non-trucking occupations."
This study provides weak evidence of an association between bladder cancer
incidence and gasoline exposure. Workers in gasoline service, after adjusting
for age and smoking, were observed to have a 30% greater risk of bladder cancer
than those not working in gasoline service (adjusted OR = 1.3, p value not
reported). Truck drivers were found to be at significant risk even after
controlling for age and smoking (adjusted OR = 2.1). This risk increased sig-
nificantly (p = 0.004) with increasing duration of employment as a trucker.
The risk among truckers who transported petroleum products, after adjusting for
age and smoking (adjusted OR = 3.6), was elevated to more than 3-1/2 times that
of non-truckers. Risks were also elevated (p > 0.05) for cab drivers (crude OR
s 2.0), bus drivers (crude = 1.5), and delivery men (adjusted OR = 1.8), all
occupations with potential gasoline exposure.
The authors' analyses did control for the confounding effects of age,
smoking, and other employment in high-risk industries or occupations. Analyses
for other potential risk factors for bladder cancer (e.g., artificial sweeten-
ers, coffee drinking, alcohol consumption) were also conducted.
There are limitations to the study. It was not possible to evaluate whe-
ther the excess risk could be attributed to diesel exhaust, gasoline exhaust,
4-10
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diesel vapors, gasoline vapors (whether leaded or unleaded), or some other
exposure. There was no quantification of gasoline vapor exposure. Some of the
observed elevations in risks for bladder cancer cases for certain occupations
may have been due to chance because of the large number of comparisons made in
this study.
Latency analyses were not conducted for occupational exposure at the
gasoline service station, or for the cab drivers, bus drivers, or delivery men.
Excluded from the study population of 303 white male cases were 86 cases (race
not reported) of lower urinary tract cancer. The authors presented no assess-
ment of the impact of this potential non-response bias.
4.1.3. Mommsen et al. (1982; 1983a, b); Mommsen and Aagaard 1983a, b; 1984);
Mommsen and Sell (1983)
Several publications have resulted from the authors' investigation of
212 bladder cancer cases (165 males and 47 females) and 259 controls (165 males
and 94 females) in a predominantly rural area in Denmark (Mommsen et al., 1982;
1983a, b); Mommsen and Aagaard (1983a, b; 1984); Mommsen and Sell (1983).
Reported here are the findings of the initial investigation of the males (1982)
and a detailed analysis of male occupational factors (1984).
The case population consisted of males, ages 42 to 85, who were newly
diagnosed with bladder cancer (91.5% invasive, 94.5% with transitional cell
carcinoma) and admitted consecutively to the University Hospital of Aarhus,
Department of Oncology and Radiotherapy, during the period September 1977 to
September 1979. Terminal and intractable cases were not referred to the
hospital and thus were excluded from the study population (Mommsen et al.,
1983b). According to Mommsen and Aagaard (1984), the case population reflects
the 2-year incidence of invasive bladder cancer among males in the area
(22,000 km2).
4-11
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Information on the cases as well as controls was obtained by means of
a questionnaire. Both cases and controls were given the questionnaire in
advance. Subsequently, cases were interviewed by the principal investigator
at the hospital following a review of the histologic specimens (Mommsen et al.,
1982, 1983b; Mommsen and Aagaard, 1984).
Population-based controls were selected from the National Register for
the region and individually matched to the cases on the basis of sex, age, and
geographic area, including the degree of urbanization. Data on 95% of the
controls were collected by telephone interview, the principal investigator
serving as the interviewer. Data on 5% of the controls (those without tele-
phones) were obtained via a mailed questionnaire (Mommsen et al., 1983b). If
after a month no reply was received, a second questionnaire was mailed; and if
after another month no response was received, another matched control was
selected. Fifteen percent of the controls were substitute controls (Mommsen et
al., 1983b).
Identical questionnaires were used for both cases and controls and soli-
cited information on education, lifetime occupational history, socioeconomic
status, medical history, family history of cancer, and subjects' use of alcohol,
tobacco products, coffee, artificial sweeteners, and drug treatments.
Mommsen and Aagaard (1984) ascertained occupational histories from the
time a subject completed school until he was selected as a study subject. A
subject was categorized as being exposed to a particular industry based upon
the job he held for the longest period of time, provided that it was held for
at least 1 year. Information on possible occupational exposures was obtained
from study subjects through the use of "non-structured questions" (Mommsen and
Aagaard, 1984).
Bivariate associations between bladder cancer and the 13 most pronounced
4-12
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independent variables were measured with the odds ratio. The 95% confidence
intervals were calculated (Miettinen, 1974). Ipsen's computer program (unpub-
lished) of the logistic regression model was used for the multivariate analyses
of the data. Independent variables were categorized as dichotomous (yes/no).
The dependent variable was risk of bladder cancer. A step-down procedure was
used to eliminate "non-informative" independent variables from the model.
Goodness-of-fit was expressed by the likelihood ratio G^. Loss of information
to the model was estimated through the increase in Sz and &62, distributed as
a chi-squared statistic with one degree of freedom (Bishop et a!., 1977).
Mommsen et al. (1982) identified the following as significant (p < 0.05)
bladder cancer risk factors in males: work with gasoline or oil (OR = 2.71,
95% CI 1.21-6.10); cigarette smoking (OR = 1.89, 95% CI 1.21-2.94); nocturia
(OR « 2.05, 95% CI 1.27-3.32); prostatic surgery (OR « 2.38, 95% CI 1.16-4.90);
history of venereal disease (OR = 2.42, 95% CI 1.01-5.82); and industrial work
(OR = 1,82, 95% CI 1.04-3.17), Work with chemical materials (OR - 1.58, 95% CI
1.0-2,49) was found to be borderline significant. Risks for petroleum or
asphalt workers were elevated (OR - 3.12) but not significantly (CI 0.91-10.75).
A similar pattern of risk was seen for use of chewing tobacco (OR = 1.65, 95%
CI 0.96-2.84) and alcohol (OR = 2.46, 95% CI 0.95-6.31).
The logistic regression analysis (Mommsen et al., 1982) revealed that
males who worked with gasoline or oil were at significantly more risk for blad-
der cancer—2-1/3 times more (estimate of relative risk = 2.32, p < 0.05) than
males who do not work with gasoline or oil even after significant confounding
factors were controlled for. Inclusion of the following variables in the
model (work with petroleum or asphalt, work with chemical materials, chewing
tobacco user, industrial worker, alcohol user, previous venereal disease, and
symptoms of cystitis) failed to significantly change the probability of blad-
4-13
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der cancer. Thus, only six risk factors—work with oil or gas, cigarette smok-
ing, nocturia, prostatic surgery, cheroot smoker, and lowest socioeconomic
level were considered significant independent risk factors for invasive bladder
cancer in this rural area of Denmark.
Mommsen and Aagard's (1984) detailed analysis of male occupational data
provided very little new information. No one job title was indicative of work
with gasoline or oil. Of the 20 exposed cases, 5 were mechanics, 3 were black-
smiths, 4 were semi-skilled workers, 2 each were printers or engineers, and 1
each was a shoemaker, tailor, stoker, or unskilled worker. Of the 8 exposed
controls, 3 were semi-skilled workers, 2 were mechanics, and 1 each was a
blacksmith, printer, and stoker. Both cases and controls averaged 27 years of
exposure to gasoline or oil. As part of this review, odds ratios were calcu-
lated (Fleiss, 1981) by job titles for workers exposed to gasoline or oil.
These data indicated that bladder cancer risks were greatest for blacksmiths
(OR » 3.25) and mechanics (OR = 2.71).
The data collection methods of Mommsen et al. (1982) and Mommsen and
Aagard (1984) are questionable. The interviewer (i.e., the principal investi-
gator) was not blind towards the status of the subject as cases. Cases were
interviewed at the hospital, the majority of the controls were interviewed
by telephone, and 5% of the controls were interviewed by a self-administered
mailed questionnaire (Mommsen and Aagard, 1984). The differences in interview
methods may well have created a bias in the response. Furthermore, exposure
data were collected in a non-uniform manner, i.e., with "nonstructured ques-
tions."
There was no quantitative measure of gasoline vapor exposure. The expo-
sure category included "gasoline or oil," and there was no attempt to assess
the effects of gasoline independent of those of oil. The job titles presented
4-14
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for the 28 exposed cases and controls make the argument-for oil or dye exposure
rather than for gasoline exposure. None of the job titles presented were for
jobs in which a gasoline occupational exposure could be inferred (i.e., gaso-
line service station attendant). Only the seven mechanics (crude OR = 2.71)
appeared to have a potential for an occupational exposure to gasoline; this
odds ratio was not adjusted for confounding variables such as smoking, and no
latency analyses were conducted.
The authors' retrospective data were analyzed as if they were prospective
data; i.e., the probability of bladder cancer was modeled rather than the
probability of exposure. Because of the small size of the study population,
the magnitude of the authors' relative risk estimate using the logistic model
may be questioned.
Thus, this study provides insufficient data to determine the carcinogeni-
city of gasoline.
4.1.4. Domiano et a!. (1985)
A case-control study was carried out by Domiano et al. on 92 white male
cases with histologically confirmed renal cell carcinoma and 1,588 white male
controls with nonneoplastic diseases admitted to Roswell Park Memorial Insti-
tute from 1957 to 1965. The age range of both cases and controls was 30 to 89.
For purposes of analysis, two age groups were created: 30 to 59 and 60 to 89;
approximately half of the controls were in each group. Patients admitted with
urogenital, circulatory, respiratory, or mental disorders were excluded from
the control population (ICD-7, 001-008, 016, 018, 022, 023, 031, 300-326, 330-
334, 400-468, 470-527, 590-637, 782-783, 786, 789, 792, 794).
At the time of admission, patients filled out a questionnaire including
occupational history, diet, and smoking habits. Cigarette smoking was measured
in terms of pack-years, the product of the number of years a person smoked and
4-15
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the average number of packs smoked per day. Occupational titles were coded
according to the U.S. Department of Commerce Alphabetical Index of Occupations,
and the Industries were coded according to the Standard Industrial Classifica-
tion Manual. An occupational title-gasoline exposure linkage system was devel-
oped based on the occupational and industrial hygiene literature. Cases and
controls were compared for "possible" exposure (employment as an operative or
laborer In refinery, construction, transportation, machinery, or petroleum
transport and storage industries) or "definite" exposure (employment in gaso-
line service stations).
Four of the 92 cancer cases (4.3%) and 122 of the 1,588 controls (7.7%)
had any exposure to gasoline (combines definitely and possibly exposed); three
of the cases were "definitely" exposed to gasoline. The age-adjusted relative
risk estimate for any gasoline exposure was a nonsignificant 0.53. All four
of the exposed cases smoked 21 or more pack-years of cigarettes. After post-
stratifying for age, risks were examined among males who smoked 21 or more
pack-years of cigarettes. The relative risk estimate for the younger smokers
exposed to gasoline was 0.90 (one exposed case); among the older smokers, renal
cell carcinoma risks for gasoline exposure were 2-1/2 times those of smokers
not exposed to gasoline (OR = 2.49, two exposed cases, p value not reported but
was calculated as 0.20 < p < 0.30, distributed as a chi-squared statistic with
one degree of freedom).
The authors hypothesized that the Interaction between heavy cigarette smok-
ing and long-term gasoline exposure may be associated with an increased risk of
renal cell carcinoma. However, because there were no males in the non-smoking
gasoline exposure group, it was not possible to quantitatively examine this
hypothesis. The data do suggest that smoking is a confounding factor for renal
carcinoma (age-adjusted OR for smoking 21+ pack-years.= 1.30, 50 exposed cases).
4-16
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This study provides limited data on the association between gasoline and
renal cell carcinoma. The numbers of exposed cases were very small (n = 3),
and while risks were elevated among the older smokers for exposure to gasoline,
they were not significantly elevated and may have occurred by chance. Further-
more, the authors' smoking category of 21+ pack-years is very broad, and thus
may not have adequately controlled for the effects of smoking among the older
smokers. The paper suggests that the authors' categorization of smoking into
the high category at 21 pack-years may be biased, as the categorization was
based on the distribution of the cases and not on the controls. The authors
provided no analysis of latency or length of employment in gasoline service
stations. Finally, it was not possible to control for the effects of other
potential gasoline service station exposures (e.g., motor oils, engine exhausts,
solvents, etc.).
4.1.5. Lin and Kessler (1981)
This case-control study of pancreatic cancer was conducted in more than
115 hospitals in five metropolitan areas of the United States: Buffalo, NY;
Detroit, MI; Miami, FL; Minneapolis-St. Paul, MN; and New York, NY.
Study subjects were identified through hospital records, including path-
ology departments. Cancer-free controls were randomly selected from among con-
temporaneous admissions to the same hospital and matched individually to the
cases on the basis of sex, race, age •(+. 3 years), and marital status (ever/
never). Patients admitted "primarily" for diabetes mellitus, pancreatitis, or
gallstones were excluded from the control population. Study subjects were per-
sonally interviewed by interyiewers blind towards the status of the study
subjects, usually in the hospital setting.
Information was collected in detail on demographic characteristics, resi-
dential history, occupations, toxic exposures, animal contacts, smoking habits,
4-17
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diet, medical history, and family history. Information on sexual practices and
urogenital conditions was collected from the male subjects. For female sub-
jects, data on marital, obstetric, and gynecologic histories were also collec-
ted. Data were not obtained on conditions diagnosed within 1 year before the
' cancer diagnosis.
Twenty-two percent of the eligible study subjects were not interviewed
because of poor health status and were therefore excluded from the study. Of
those remaining, approximately 86% of both males and females agreed to partici-
pate. The final study population consisted of 67 male pancreatic cancer cases
and 42 female pancreatic cancer cases and their matched controls.
The chi-squared statistic and the t-test were used to test for signifi-
cant differences between the cases and their controls. Dose-response effects
were evaluated using the odds ratio as the estimate of relative risk. The
odds ratios were calculated by adding one-half to each non-zero cell. Smoking
exposure histories were evaluated with the use of a matched-pair analysis.
Male pancreatic cancer cases were significantly more likely than the
controls to have been employed in occupations involving close exposure to
gasoline (e.g., service stations and garages) or in the dry cleaning business
(32.8% vs 14.9%, p < 0.05). This odds ratio was not presented; however, as
part of this review a crude odds ratio of 2.79 was calculated (Fleiss, 1981)
for males occupationally exposed to gasoline or employed in the dry cleaning
business. This risk appeared to be positively associated with increasing
duration of exposure. For those exposed 3 to 5 years, the risk was 1.27; for
those exposed 6 to 10 years, the risk was 3.80; and for those exposed 10 or
more years, a significant fivefold risk (OR = 5.07; p value not reported) was
observed. (A p value for a test of linear trend was not reported.)
Decaffeinated coffee drinking (p < 0.01) and wine drinking (p < 0.05) also
4-18
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occurred more frequently among male cases 1n comparison to the male controls.
Neither odds ratios nor the data with which to calculate odds ratios were
reported.
Among females, significantly more cases than controls were identified with
a history of oophorectomy or myomatosis, drinking caffeine-free coffee, and
heavy cigarette smoking (_>_ 10 per day). Odds ratios were not presented; how-
ever, using the authors' data, it is possible to calculate a crude odds ratio
of 3.15 for females occupationally exposed to gasoline or employed in the dry
cleaning business. This suggests an elevated, although not significant, risk
for female workers.
This study provides an inadequate amount of data upon which to evaluate
the association between gasoline vapors and the risk of pancreatic cancer.
While the authors did evaluate the risks for occupational exposure to
gasoline-related occupations, no quantifications of gasoline vapor exposures
were included. In addition, no analyses were presented for the effects of
employment in the gasoline service occupations independent of the effects of
employment in the dry cleaning industry. Thus, it is not possible to deter-
mine if the increase in risk observed for this occupational exposure was due
to employment in gasoline occupations, dry cleaning occupations, or some com-
bined exposure to both. However, workers 1n dry cleaning occupations have not
previously been identified as being at an excess pancreatic cancer risk.
Although the authors did find a significant association of pancreatic can-
cer and cigarette smoking among females, no association was observed for males.
This finding is inconsistent with numerous other studies on the relationship be-
tween smoking and pancreatic cancer (U.S. Public Health Service, 1982). Final-
ly, the authors' analyses failed to control for the simultaneous effects of
significant confounding variables. Hence, this study is considered inadequate.
4-19
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4.1.6. L1n and Kessler (1979)
Lin and Kessler also reported (as a proceedings abstract) on a case-rcon-
trol study of testicular cancer in 410 white and black males (205 each cases
and controls). The cases were selected from recently discharged hospital
patients. The controls were "similar" demographically to the cases; however,
the method of control selection was not specified.
The authors reported that the cases were significantly (p value not re-
ported) more likely to be employed as gasoline station attendants, garage
workers, truck drivers, firemen, smelter workers, or metal heaters. The cases
and controls did not differ with respect to urban/rural residence, smoking
practices, education, religion, or sexual practices. Additional details were
not presented.
The lack of any methodologic detail precludes consideration of these data.
Thus, this study is considered an inadequate basis upon which to determine the
carcinogenicity of gasoline.
4,1.7. Hi!ham (1983)
Mil ham analyzed all Washington State death certificate records for white
male residents (429,926) for the years 1950-79 and white female residents
(25,066) for the years 1974-79, ages 20+.
Occupational data were obtained using the death certificate item "usual
occupation during most of lifetime." Male records for the years 1950-71 were -
abstracted, coded, keypunched, and then read onto magnetic tape for computer
analysis. Male records for the years 1972-79 and all female records, excluding
those with "housewife" listed as the usual occupation, were routinely abstrac-
ted, coded, and entered into the computer within 30 days of the date of death.
Occupations were coded with a modified U.S. Bureau of the Census code. Data
were not available for 3% of the deceased male population, e.g., occupations
4-20
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listed as retired, unknown, etc.
For males whose cause of death was urinary bladder cancer or Hodgkin's
disease, an interview with the decedent's next of kin was conducted to assess
the accuracy of the occupational information on the death certificate. The
next of kin gave the identical occupation as noted on the death certificate
75% of the time, a related occupation 10% of the time (e.g., plywood mill
worker versus mill worker), and a completely different occupation 15% of the
time. Death certificate information was also validated through union records
for 100 engineers. Of these, all but two were correctly listed on the death
certificate as an engineer.
Cause-of-death information was coded to the 7th ICD, and results were
available for 160 causes of death. Age- and year-of-death standardized pro-
portionate mortality ratio (PMR) analyses were used for both males and females.
Expected deaths were computed for each year of the study using that year's
mortality experience for the State of Washington as the standard. Expected
deaths were then summed over 5-year age intervals and rounded to the nearest
whole number before the results were printed. Differences in the observed and
expected values were tested at the 1% and 5% level with a chi-squared statis-
tic with one degree of freedom. PMRs were reported for each decade (1950-59,
1960-69, 1970-79), for the total 30-year period (1950-79), for those 20-64
years old at the time of death, and for those in each 5-year age interval.
Significance testing was done only on observed values of 6 or more. Excluded
from significance testing were PMR values for each 5-year age interval. Un-
less specified, all results reviewed here are for the period 1950 through 1979.
i
Cause-of-death analyses were presented for 219 occupational categories
for males and 51 occupational categories for females. Two of the male occupa-
tional categories (gas station/garage owners and attendants, and fuel oil and
4-21
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gasoline truck drivers) were considered to have workers with gasoline exposure,
and two additional categories (fuel oil dealers and workers, and auto mechanics
and repairmen) were considered to have workers with petroleum products exposure
and potential gasoline exposure.
PMR results for the malignant diseases by the four occupational categories
are summarized in Table 4-1. Reported by the author but not presented here
are statistically nonsignificant cancer excesses of less than 20%, nonsignifi-
cant findings In which the observed numbers of death were less than three, and
nonsignificant deficits.
There were 2,786 observed deaths among the gas station/garage owners and
attendants during the period 1950-79. The proportion of malignant neoplasm
deaths among this group was approximately equal to the proportion observed
among all white male Washington State decedents (PMR = 97, observed = 480, p >
0.05). A statistically significant (p < 0.05) excess was observed for cancers
of the bladder and other urinary organs for those who died during the periods
1950-59 (PMR « 219, observed - 4) and 1960-69 (PMR - 185, observed = 6); how-
ever, for the period 1970-79, a deficit was observed (PMR * 75, observed » 8,
p > 0.05).
Significant excesses were not observed for any other malignant diseases;
however, significant (p < 0.05) deficits were observed for cancer of the diges-
tive organs and peritoneum (PMR * 82, observed = 124) and cancer of the large
intestine, except rectum (PMR = 68, observed = 29).
PMRs were elevated (p > 0.05) (those less than 120 are not presented here)
for malignant neoplasms of the mouth, excluding the floor of the mouth, sali-
vary gland, tongue, and lip (PMR = 209); pharynx, unspecified (PMR = 194);
liver, secondary and unspecified for the periods 1960-69 (PMR = 144) and 1970-
79 (PMR » 137) only; pancreas for the periods 1960-69 (PMR = 128) and 1970-79
4-22
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TABLE 4-1. SUMMARY OF PHR CANCER FINDINGS FOR FOUR OCCUPATIONAL CATEGORIES WITH GASOLINE OR PETROLEUM PRODUCTS EXPOSURE*
(Milham, 196))
(X>
1 —
Gas station owners/
attendants
1950- I960- 1970-
Type of canc«r 1959 1969 1979
All malignant neoplasms 94 100 95
Buccal cavity/pharynx - - 144
Mouth -
Tongue -
Pharynx - 296
Oral masopharynx -
Digestive organs/
peritoneum -
Esophagus ...
Stomach - - -
Large intestine -
Small Intestine
Rectum
Liver (primary) -
Liver -
Liver (secondary,
unspecified) . - 144 1)7
Pancreas - 128 126
Respiratory system - - -
Larynx - - 191
Trachea, bronchus,
lung -
Thoracic organs
(secondary) - - -
Genitourinary organ*
Prostate
Testls - 42)
Bladder 219* 185* 75
Kidney 125 - 156
-
1950-
1979
97
121
209
-
194
141
82«
-
_
68«
-
-
-
-
117
119
12)
12)
-
247
161
144
122
Fuel oil/qas truck drivers
1950- I960- 1970- 1950-
1959 1969 1979 1979
106 108 117 ID/
l))*b
160
_
- . -
-
~
151 - 159 1)4
288
195 165
181 145
_
150
.
_
_
_
14) - 117
.
DO 121 I20d
_
-
-
1)8
177
Fuel oil dealers/workers
1950- I960- 1970- 1950-
1959 1969 1979 1979
99 109 III 107
27)« - DO
-
_
282
-
-
.
DO - - 117
.
155 107
156=
.
-
155 129 - 125
_
-
_
_
\I2* DO - DO
_
127 182 129
150 88
Auto mechanics/repairmen
1950- I960- 1970- 1950-
1959 1969 1979 1979
III 107 101 104
154 - - 89
_
124°
206 125 144
24IC
_
181 2I2« 126 I6S«
126°
.
184
_
17) - - 71
24) -
.
288*/
2l8f
I45« - I22« 12)"
197 - 15) 133
155* - 122* 124"
_
-
.
129 166 - 119
- - - -
(continued on the following page)
-------
TABLE 4-1. (continued)
6*s station owners/
attendants
Typ* of cancer
1950-
1959
1960-
1969
1970-
1979
_____ FuaJ oil/gastruck drivers
1950- (950- I960- 1970- 1950-
1979 1959 1969 1979 1979
Fual oi I dealersA»ork«rs
1950- I960- 1970- 1950-
1959 1969 1979 1979
Auto mcchanics/repairmgn
1950- I960- 1970- 1950-
1959 1969 1979 1979
Brain
122
167
140 I9J«b
Man-Mlanoma skin
HelcnoM skin -
157
206
152
L««phatic/h«iMtopoiatic
•I?"
r\3
tissues 120
Hodgktn's disease 191 148
LyMpbo- and
reticulosarccmas -
Ottwr lyRf>haMS - 224
Huftipla wye Iowa - -
UokMia/al*uk«*ia 160 -
Kyelold leukMila 207 175
Lynphatic leukemia -. - -
Acute laukenia - 128
Ottwr laukaouas -
* p < 0.05.
** p
-------
(PMR = 126); larynx (PMR = 191) for the period 1970-79; testis for the period
1960-69 (PMR = 423) (the data for the period 1970-79 were not readable); kid-
ney (1950-59 PMR = 125; 1970-79 PMR = 156); non-melanoma skin (PMR = 157);
Hodgkin's disease (1950-59 PMR = 191; 1960-69 PMR = 148); other lymphomas
(1960-69 PMR = 224); leukemia and aleukemia (1950-59 PMR = 160); and myeloid
leukemia (1950-59 PMR = 207).
Several of the nonmalignant diseases exhibited a significant excess or
deficit among gasoline station workers (p < 0.01 unless specified): asthma
(among those ages 20-64 only, PMR = 223, observed = 10); diabetes mellitus (PMR
= 142, observed = 55); diseases of the circulatory system (PMR = 109, observed
= 1,332); arteriosclerotic heart disease, including coronary disease (PMR =
109, observed = 1,048); diseases of the respiratory system (PMR = 79, observed
= 126); pneumonia (PMR = 71, observed =45, p < 0.05); duodenal ulcer (PMR =
193, observed = 20); cirrhosis of the liver without alcoholism (PMR = 58,
observed = 28); cirrhosis of the liver with alcoholism (PMR = 31, observed =
6); and accidental falls (PMR = 37, observed =11).
There were 73 cancer deaths of a total of 334 deceased males whose usual
occupation was fuel oil or gasoline truck driver (PMR = 113, p > 0.05). Among
those ages 20 to 64, a significant excess in total cancer was observed (PMR =
133, observed = 48, p < 0.05). A significant excess was also observed for
diseases of the arteries (PMR = 176, observed = 15, p < 0.05) and for motor
vehicle accidents (PMR = 214, observed = 24, p < 0.01).
Elevated, although not significantly, were PMRs for cancers of the buccal
cavity and pharynx (among those ages 20 to 64 PMR = 244); digestive organs and
peritoneum (1950-59 PMR = 151; 1970-79 PMR = 159); esophagus (PMR = 288);
stomach (1970-79 PMR = 195); large intestine, except rectum (1970-79 PMR =
181); rectum (PMR = 150); respiratory system (1960-69 PMR = 143); primary lung,
4-25
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bronchus, and trachea (1960-69 PMR = 130; 1970-79 PMR = 121); bronchus and lung
(among those 20 to 64 PMR = 155; 1960-69 PMR = 153); kidney (PMR = 177); blad-
der and other urinary organs (PMR = 138); lymphatic and hematopoietic tissues
(1960-69 PMR » 158); and leukemia and aleukemia (PMR - 145).
There were 1,554 deaths among white males whose usual occupation was fuel
oil dealers and workers; 305 of these deaths were due to a malignant neoplasm
(PMR = 107, p > 0.05). Significant cancer excesses were observed for cancers
of the buccal cavity and pharynx (1960-69 PMR = 273, observed = 8, p < 0.01),
prostate (1950-59 PMR = 172, observed = 13, p < 0.05), and lymphatic and hema-
topoietic tissues (1970-79 PMR = 180, observed = 19, p < 0.01). Cancer of the
brain was significantly elevated among those between the ages of 20 and 64 at
the time of death (PMR = 193, observed = 9, p < 0.05). There were no signifi-
cant cancer deficits observed.
Statistically nonsignificant cancer excesses (p > 0.05) of 120 or above
were observed for several forms of cancer: cancers of the pancreas (1950-59
PMR * 155; 1960-69 PMR = 129), prostate (1950-59 PMR = 130), bladder and other
urinary organs (1960-69 PMR = 127; 1970-79 PMR - 182), and lympho- and reticu-
losarcomas (1970-79 PMR = 300); Hodgkin's disease (1960-69 PMR - 350); other
lymphomas (1970-79 PMR = 334); multiple myeloma (1970-79 PMR » 208); and leu-
kemia and aleukemia (1950-59 PMR = 131).
Nonmalignant diseases observed at significant levels (all p values were
less than 0.05 unless specified) were infective and parasitic diseases (PMR
» 46, observed =6); asthma (PMR = 203, observed =10); psychoses (PMR = 275,
observed » 6, p < 0.01); paralysis agitans (PMR = 237, observed = 10, p <
0.01); diseases of the circulatory system among white males ages 20 to 64 (PMR
* 115, observed * 272); arteriosclerotic heart disease, including coronary dis-
ease among males ages 20 to 64 (PMR = 119, observed = 231, p < 0.01), diseases
4-26
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of the respiratory system (PMR - 69, observed = 68, p < 0.01); pneumonia (PMR
- 66, observed = 26), other diseases of the lung and pleura! cavity (ICD 527)
(PMR = 69, observed = 28); and for the period 1970-79, other diseases of the
urinary system (PMR = 215, observed =8).
Among the white males whose usual occupation was automobile mechanics or
repairmen, there were 3,445 observed deaths; 677 of these were cancer deaths
(PMR = 104, p > 0.05). Esophageal and respiratory system cancers both exhi-
bited a significant excess (PMR = 163, observed = 22, p < 0.05 and PMR = 123,
observed = 255, p < 0.01, respectively). The overwhelming majority of the
respiratory system cancer deaths were from primary cancer of the bronchus,
trachea, and lung (PMR = 124, observed = 210, p < 0.01); however, nonsigni-
ficant excesses were observed for cancers of the larynx (PMR = 133). Excesses
were observed for all of the lymphatic and hematopoietic tissue cancers, some
being significant: lymphatic leukemia (ICD 204.0) (1960-69 PMR » 283, observed
= 8, p < 0.01) and other lymphomas (ICD 202 and 202.2) for the period 1970-79
only (PMR = 198, observed = 10, p < 0.05). Nonsignificant (p > 0.05) excesses
were observed for Hodgkin's disease (1950-59 PMR = 196), myeloid leukemia (ICD
204.1) among those ages 20 to 64 (PMR = 181), acute leukemia (ICD 204.3) (1970-
79 PMR = 120), and other unspecified leukemias (ICD 204.4) among those ages
20 to 64 (PMR = 284).
The proportion of cancer deaths among automobile mechanics was elevated
nonsignificantly (p > 0.05) for several other kinds of cancer: buccal cavity
and pharynx (1950-59 PMR = 154); tongue among those ages 20 to 64 (PMR = 124);
oral mesopharynx among those ages 20 to 64 (PMR = 241); pharynx, unspecified
(1950-79 PMR = 144; 1970-79 PMR = 125, observed =2); stomach among those ages
20 to 64 (PMR = 126); small intestine, including duodenum (PMR = 184); liver
(1950-59 PMR = 243); pancreas among those ages 40 to 44 (PMR = 288) and 45 to 49
4-27
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(PMR « 218); and bladder and other urinary organs for the years 1950-59 (PMR =
129) and 1960-69 (PMR = 166).
Statistically significant excesses (p < 0.05) were also observed for mul-
tiple sclerosis {PMR = 233, observed = 10, p < 0.01), paralysis agitans (PMR =
177, observed = 14), chronic rheumatic heart disease (PMR = 139, observed =
41), bronchitis with emphysema (1970-79 PMR = 188, observed = 10), other dis-
eases of the lung and pleura! cavity (1970-79 PMR = 125, observed =81), and
hernia of the abdominal cavity (PMR = 285, observed = 9, p < 0.01).
There are several limitations to this study. The major problem is the
questionable validity associated with the use of PMRs as a method of analysis.
In addition, workers in each of the four occupational categories were potenti-
ally exposed to gasoline; however, they were also potentially exposed to other
petroleum products, such as diesel fuel oil, home heating oil, motor oils, and
solvents, as well as to engine exhausts. It was not possible to control for
these potential confounding exposures or to quantify gasoline exposure. Due
to data constraints, the analyses by latency or length of employment were not
carried out.
The validation study of death certificate information suggested that 15%
of all death certificates had an unreliable occupation listed as the "usual
lifetime occupation." Although this is probably a random occurrence, the small
number of observed deaths for a particular malignant disease may be unduly
influenced; thus, a PMR may be under- or overestimated for a particular job
category.
Finally, there was no control for other confounding risk factors such as
smoking. Thus, this study provides an insufficient basis upon which to assess
the association of gasoline and cancer risk.
4-28
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4.2. EPIDEMIOLOGIC STUDIES OF WORKERS IN THE PETROLEUM INDUSTRY
4.2.1. Mortality Studies of Workers in the Petroleum Refining Industry
4.2.1.1. Tabershaw-Cooper Associates, Inc. (1974 Unpublished, 1975 Unpub-
lished)—On behalf of the American Petroleum Institute (API), Tabershaw-Cooper
Associates, Inc. (1974) conducted a retrospective cohort mortality study of
petroleum refinery workers at 17 refineries. The refineries were sampled from
the 251 United States refineries listed in the 1971 Census of the Oil and Gas
Journal. The sample was designed to give a "reasonably representative distri-
bution" of the refinery population with respect to location, ownership, and
size. The study population consisted of all hourly employees (excluding cler-
ical) who worked in one of the refineries for at least 1 year between January
1, 1962, and December 31, 1971. Because of missing records, only pensioners
were included from Refinery No. 5. The final cohort consisted of 20,163 sub-
jects, representing 137,153 person-years of observation.
Information on each study subject was obtained from plant personnel records
and included date of birth, date of hire, most recent job title, date of termi-
nation or retirement, date and place of death for those known to have died,
and, for terminated employees, their last known address. Race information
was not available on most employees. The authors estimated that 91.9% of the
cohort was white (including Mexican and Latin Americans), 7.9% were black, and
0.2% were other. These estimates were based on information received from five
of the refineries on the race distribution of their current work forces.
Exposure was categorized as high, medium, or low with respect to hydrocar-
bon exposure by a refinery safety engineer. The high category (Category A)
included laboratory, maintenance, and salvage recovery jobs. Workers in this
category would have had exposure to gasoline. The low category contained plant
security, utility, purchasing, and motor transport jobs. Some of the workers
4-29
-------
1n this category (I.e., motor transport) would have had exposure to gasoline;
others probably would have not. All other jobs, including laborers, were
classified as medium exposure; individuals in this category had potential for
gasoline exposure.
Vital status was determined as of December 31, 1971. Cohort members Who
had terminated employment or retirees whose vital status was unknown were
traced using telephone books, the U.S. Post Office, and state drivers license
bureaus. Six percent (1,120) were lost to follow-up.
In an effort to ascertain vital status for all cohort members, the authors
requested that the Social Security Administration (SSA) determine, for each
worker lost to follow-up, whether contributions were still being made; whether
benefits were being received; and whether a death claim had been filed, and if
so, where and when. This follow-up study (Tabershaw-Cooper Associates, Inc.,
1975) resulted in the successful tracing of 99% of the original cohort, repre-
senting 5,499 person-years of observation. A total of 1,194 deaths were ascer-
tained; death certificates were acquired for all but 10 of these. The authors
did not indicate which revision of the ICD was used to code the death certifi-
cates.
Standardized mortality ratios (SMRs) were calculated, comparing the ob-
served mortality experience of the cohort to what was expected, by using the
United States male-, calendar-, time-, age-, and cause-specific mortality as
the standard rate. It was not possible to determine if race was assumed to be
white for the calculations of the expected numbers. SMRs were tested for sta-
tistical significance at the a = 0.05 and a = 0.01 levels using an adaptation
of a formula of Chiang (1961).
Current employees represented 68% of the cohort; the others were retired,
18%; terminated, 11%, and deceased 4%. Approximately 34% of the cohort were
4-30
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age 41 or younger at the end of the study period; about 31% were 57 or older.
Sixty percent had 20 or more years of service, and only 28% were employed for
less than 10 years.
Results were reviewed for the original study (Tabershaw-Cooper Associ-
ates, Inc., 1974) and the SSA updated study (Tabershaw-Cooper Associates, Inc.,
1975); they were generally the same. Reported here are the results for the SSA
updated study.
For the total cohort the SMR for all causes of death was 69 (observed =
1,194); this was statistically significant (p < 0.01) and suggests a healthy-
worker effect for this refinery population. The SMR for all cancers was also
significantly low (SMR = 83, observed = 275, p < 0,01). Small statistically
nonsignificant excesses were observed for lymphoroas (SMR - 123) and malignant
neoplasms of the genital organs (SMR = 111). No other excesses were reported.
Several causes of death had significant deficits in mortality including cancers
of the buccal cavity and pharynx (SMR = 58, observed = 7» p < 0.05), the
respiratory system (SMR = 82, observed = 93, p < 0.05), and urinary organs (SMR
= 35, observed = 6, p < 0.01). Cause-specific SMRs were not reported for 32
cancer deaths. It appears that these deaths were for miscellaneous cancer
sites including cancers of the bone, skin, brain and central nervous system
(CNS), and other unspecified sites.
Nonmalignant causes of death for which significant (p < 0.01) deficits
were observed were: diabetes mellitus (SMR = 45, observed = 11), vascular
lesions affecting the CNS (SMR = 53, observed =57), arteriosclerotic heart
disease (SMR - 84, observed = 511), nonrheumatic endocarditis (SMR = 24, ob-
served =7), hypertensive heart disease (SMR = 30, observed =11), influenza
and pneumonia (SMR = 31, observed = 11), cirrhosis of the liver (SMR = 47,
observed =24), symptoms of senility and ill-defined conditions (SMR = 56,
4-31
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observed » 14), motor vehicle accidents (SMR = 53, observed = 31), other
accidents (SMR = 61, observed = 39), suicide {SMR = 63, observed = 24), and
homicide = 52, observed = 10).
The authors carried out analyses of several subcohorts, first dividing the
cohort into those hired before the starting date of the study (i.e., 1962) and
those hired later. The mortality pattern for the former group (consisting of
7B% of the cohort) was identical with that of the total cohort. Again, the
only excesses were for lymphomas (SMR = 126) and cancer of the genital organs
(SMR « 106); these were not statistically significant. For those hired after
1962 the numbers of observed deaths were very small, making cause-specific
Interpretations difficult. A statistically significant deficit was observed
for all causes of death (SMR = 39, observed = 13, p < 0.01) and an excess of
E5% (SMR = 125) was observed for all cancer deaths; however, the latter was
based on only four observations and was not significant.
Mortality patterns among those hired before 1952 (i.e., the subcohort with
approximately 10 or more years of occupational exposure) were generally similar
to those of the total cohort; the only excess observed was for lymphomas (SMR =
129, p > 0.05). Cancer of the genital organs was observed at expected levels
(SMR = 103, p > 0.05); all other causes of death considered by the authors were
deficits, Including the SMRs for all causes of death (SMR = 70, observed =
1»123, p < 0.01) and all cancers (SMR = 82, observed = 261, p < 0.01).
Among those hired after 1952, a significant (p < 0.01) deficit was observed
for all causes of death (SMR =61, observed =71); for all cancers the SMR was
observed at expected levels (SMR ~ 99, p > 0.05). However, excesses (p > 0.05)
were observed for cancers of the buccal cavity and pharynx (SMR = 424), diges-
tive organs and peritoneum (SMR = 156), and genital organs (SMR = 303). These
were based on only a few observations (2, 5, and 2, respectively).
i ' 4-32
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The SMR for all causes of death was significantly (p < 0.01) low for each
of the three hydrocarbon exposure categories (high, SMR = 67, observed = 499;
medium, SMR = 69, observed = 528; low, SMR = 80, observed = 167). Risks for
all cancers were also low, but were only significant (p < 0.01) among workers
in the medium exposure category (medium, SMR = 81, observed = 120; high, SMR =
87; low, SMR = 77). If one assumes that the age distribution of workers in
the three exposure categories was similar, then SMRs across exposure categories
may be compared. A positive trend associated with increasing exposure was
observed for cancer of the genital organs (high, SMR = 136; medium, SMR = 117;
low, SMR = 0); however, these point estimates were not statistically signifi-
cant. Statistically nonsignificant excesses were also observed for lymphomas
among workers in the high exposure category (SMR = 129) and in the low category
(SMR = 170), and for leukemia and aleukemia among workers in the low exposure
category (SMR = 271). No overall pattern of risk associated with increasing
exposure was observed for the remaining site-specific cancers. These SMRs
were lower than 100 in all instances and were significantly low for respira-
tory system cancer among those in the medium exposure category (SMR = 76,
observed =- 39). The overwhelming majority of the SMRs for the nonmalignant
diseases were lower than 100 regardless of exposure category; a few were ob-
served to be significant deficits, but no overall pattern related to exposure
could be discerned.
The authors also evaluated risks for males who had at least 20 years of
exposure and for whom the "20th year of exposure occurred at least 10 years
before" the end of the study. These 5,145 workers were all hired before 1943.
Cancer risks for this subcohort were generally the same as those of the total
cohort except that the excess lymphoma mortality observed in the total cohort
(SMR = 123) appeared to disappear in this subcohort (SMR = 93). The deficit
4-33
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observed among the total cohort for digestive system cancer (SMR = 86) was
observed to be significant (p < 0.05) for this subcohort (SMR = 76, observed
=43). No cancer excesses were observed.
This large study had excellent follow-up (99%), and death certificates
were obtained for all but 0.8% of the deceased cohort members. Analyses were
undertaken for exposure categories for which some job title information was
available, and a latency analysis was also conducted. The period of follow-up,
however, was short, only 10 years. This is important .considering the young age
of the cohort; approximately 70% were age 56 or younger at the time of vital
status ascertainment. There was no control for confounding variables such as
other chemical exposures and smoking. Considering that SMRs for all smoking-
related diseases were lower than what was expected (many were significantly
lower), smoking is not considered to be a serious confounder in these data.
The authors calculated their SMRs based upon the mortality experience of
males, but females were not explicitly excluded from the cohort. If the study
population did include females, then risks for the total cohort may be biased.
It was not possible to determine if SMRs were based upon race-specific U.S.
mortality figures. Since the authors estimated that 8.1% of the cohort was
non-white, risks for the total cohort may be either overestimated or under-
estimated.
It was not possible to determine if the cause-of-death information was
coded by a trained nosologist. This is important because the study period
spanned two revisions of the ICD, and a comparability problem between ICD
revisions may be present in the data.
The major problem with this study, as well as with the other petroleum
refinery studies, is that it is not possible to determine the quantitative
gasoline exposure from the available information. Although it is known that
4-34
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many of the workers had the potential for gasoline exposures it is not known
how many workers were exposed, what their individual mortality outcome was,
or for how long or at what levels they were exposed to gasoline. Thus, this
study provides insufficient evidence to associate gasoline exposure with cancer
risks.
4.2.1.2. Hanis (1977)--Hanis conducted a retrospective cohort mortality study
of employees of the Imperial Oil Company, Ltd. of Canada. The cohort included
all active male employees who were employed at least 1 year during the 10-year
period 1964-73 and all terminated, including retired, male employees who were
employed at least 5 years during the study period. Excluded from the study
population were 6,681 short-term employees (i.e., male terminated employees
with less than 5 years' service and males actively employed by the company but
who had worked for the company less than 1 year during the study period). Also
excluded from the final study population were 19 annuitant deaths for whom
exposure information was missing from the company records (one of these males
was identified as an intestinal cancer death). Thus, of the 21,732 males
initially identified as potential cohort members, only 15,032 (120,636 person-
years of observation) were included in the final study population.
Employees lost to follow-up were those who left the company prior to being
vested in the pension plan, 5.8% (865). Employees vested in the pension plan
were those who terminated prior to January 1, 1966, and who had at least 15
years of service at the time of termination, and those who terminated on or
after January 1, 1966, but who had at least 10 years of service.
Deaths were identified through company medical department records. Cause-
of-death information was verified through provincial registrars, the Vital Sta-
tistics Section of Statistics Canada, and through the U.S. Department of Health,
Education, and Welfare for those employees who subsequently died in the United
4-35
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States. Not verified were 18 other foreign deaths. Of the 1,551 deaths that
were identified, cause-of-death information could not be verified for 1.6% (25)
of these. Cause-of-death information was subsequently receded to the 8th
revision of the ICD. It could not be determined if the receding was done by a
trained nosologist.
The company supplied information on each study participant on computer
tapes for the time periods 1964-68 and 1969-73. These data included name,
employment number, department number, job title (e.g., warehouseman), job
category (e.g., professional, administrative), age, and years of service. The
1969-73 data also contained information on employment status (active, retired,
or terminated), retirement date, and date of death. Information on decedents
was supplied on punched cards and included name, employee number, department
number at time of last employment, date of birth, province of death, date of
death, cause of death as coded on the death certificate, age at death, and
whether the information was verified or not.
Ten exposure categories were used to define daily exposure to crude petro-
leum, gas or breakdown products: (1) refinery, exposed; (2) refinery, non-
exposed; (3) non-refinery, exposed; (4) non-refinery, non-exposed; (5) mixed
history of exposure/non-exposure; (6) moderate exposure group; (7) mixed his-
tory refinery, exposed/non-refinery, exposed; (8) mixed history refinery, non-
exposed/non-refinery, non-exposed; (9) not enough information for a definition;
and (10) no information available. An employee was classified by the company
as a refinery worker on the basis of his department number.
The mortality experience of the oil company employees was compared to that
of the Canadian population, SMRs were calculated using the 1969 sex-, age-,
and cause-specific mortality rates to calculate the expected number of deaths.
Internal comparisons of the refinery population to the non-refinery population
4-36
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were made using the sex-, age-, and cause-specific death rates of the non-
refinery population as the standard. Causes of death excluded from the pre-
sentation of SMR results were cancers of the buccal cavity and pharynx; the
esophagus and stomach; other respiratory organs (1CD-8 160, 161, 163); the
bone, connective tissue, and skin (ICD-8 170-174); and other unspecified sites
(ICD-8 190-199).
The author did not test for statistical significance of SMR results. As
part of this review, p values for SMRs were calculated as a one-tailed exact
test assuming a Poisson distribution (Gustafson, 1984). Significance testing
was at the a = 0.05 level.
A majority (78%) of the population was present in 1964 at the beginning of
the study period. Nearly 80% of the cohort was under the age of 65 at last
observation; approximately 30% were under the age of 40. Over half the popula-
tion (52%) was employed for 20 or more years with the company. Eight percent
of the deaths occurred in the retired personnel; over 50% of the cancer deaths
occurred in workers at the Quebec or Ontario sites.
The SMR for all causes of death (SMR = 83.9, observed = 1,511) was signi-
ficantly (p < 0.01) lower than the mortality experience of the Canadian popu-
lation, demonstrating the "healthy worker" effect. Significant (p < 0.01) SMR
deficits were observed for all cancer deaths (SMR - 82.2, observed = 301),
diseases of the respiratory system (SMR = 69.4, observed - 90), and accidents,
poisonings, and violent deaths (SMR = 38.6, observed = 59). SMR deficits (p <
0.05) were also observed for diseases of the circulatory system (SMR = 94.2,
observed = 905) and for lymphatic and hematopoietic system cancers (SMR = 69.7,
observed = 25). An excess in mortality of 20% or more was not observed for any
of the malignant diseases.
All additional analyses of the cohort's mortality experience were limited
4-37
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to males 40 and older (82,057 person-years of observation), as only 1.7% of the
deaths occurred in males younger than 40.
To examine the mortality experience for geographic differences, four geo-
graphic categories were established: (1) the Atlantic Provinces, including Nova
Scotia, New Brunswick, Prince Edward Island, and Newfoundland; (2) Quebec and
Ontario; (3) the Western Provinces of Alberta, Saskatchewan, Manitoba, and
British Columbia; and (4) others including the Northwest Territories, offshore
drilling personnel, foreign subsidiaries, and affiliates. The mortality ex-
perience of the four areas was generally similar to that of the total Canadian
population. Significant deficits were observed for all causes of death for
each of the areas: Area 1 SMR = 86.6, observed = 153, p < 0.05; Area 2 SMR =
91.4, observed = 920, p < 0.05; Area 3 SMR = 76.3, observed = 367, p < 0.01;
and Area 4 SMR = 67.7, observed = 43, p < 0.05). Significant deficits were
observed for all cancer deaths in the Western Provinces (Area 3 SMR =75.0,
observed 79, p < 0.01). Deficits for all cancer deaths were also observed for
the remaining areas, but these were not observed at significant (p < 0.05)
levels (Area 1 SMR » 94.1, Area 2 SMR » 83,7, and Area 4 SMR - 53.6).
Statistically significant deficits or excesses were not observed for any
of the specific causes of death among workers in the Atlantic Provinces (Area
1); however, a 28% excess was observed for cancer of the digestive organs
(ICD-8 155-159), excluding cancer of the intestines and rectum (SMR = 128.5).
Workers in Area 2 were considered to have significantly lower mortality
than the population of Ontario and Quebec for diseases of the respiratory sys-
tem (SMR = 78.8, observed = 56, p < 0.05); cancers of the trachea, bronchus,
and lung (SMR = 62.6, observed = 44, p < 0.01); cancers of the lymphatic and
hematopoietic system (SMR = 49.5, observed = 9, p < 0.05); and accidents, pos-
sonlngs, and violent deaths (SMR * 40.2, observed = 24, p < 0.01). Excesses
4-38
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(p < 0.05) were observed for cancers of the digestive organs, excluding intes-
tines and rectum (SMR = 128.5, observed = 23), and for cancers of the urinary
bladder and kidney (SMR = 134, observed =11).
Workers in the Western Provinces (Area 3) were observed to have signifi-
cant deficits for diseases of the circulatory system (SMR - 78.6, observed =
213, p < 0.01)9 diseases of the respiratory system (SMR - 57.3, observed = 209
p < 0.05), cancer of the Intestines and rectum (ICD-8, 152-154) (SMR = 42.5,
observed = 6, p < 0.05), and accidents, poisonings, and violent deaths (SMR =
42.1, observed = 15, p < 0.01). Excesses above 20% were not observed.
Workers in the other areas (Area 4) were observed to have a favorable
mortality experience in comparison to the total population for these other
areas. SMRs were lower than 100 for all reported causes except for cancers of
the trachea, bronchus, and lung (SMR = 111.4). None of these was observed at
significant levels.
The author next compared mortality patterns for the exposed (i.e., males
who were daily exposed to crude petroleum, gas, or breakdown products regard-
less of whether they worked in the refineries) to those of the nonexposed.
There were 6,523 employees in this subcohort of exposed persons, representing
50,534 person-years of observation. The calculations for the expected number
of deaths were based on the mortality rates of the nonexposed.
The mortality experience of the exposed oil company employees was very
different from that of the nonexposed oil company employees. Significant (p <
0.01) excesses were observed for all causes of death (SMR = 127, observed =
1,085); all cancer deaths (SMR = 134, observed 215); diseases of the circula-
tory system (SMR = 115, observed = 644); diseases of the respiratory system
(SMR = 168, observed = 71); cancer of the trachea, bronchus, and lung (SMR =
211, observed = 67); and accidents, poisonings, and violence (SMR = 764, ob-
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served - 42). A more than 40% excess was observed for cancer of the urinary
bladder and kidney (SMR = 147, p > 0.05).
SMRs were not computed for stomach and esophageal cancer or for cancers of
the bone, connective tissue, and skin. The author's descriptive statistics do
suggest that esophageal and stomach cancer are two times more frequent among
the exposed population as compared to the nonexposed (12.9% versus 6%), and
that cancers of the bone, connective tissue, and skin are more than three times
as frequent among the nonexposed (8.3% versus 2.3%) as compared to the exposed.
The author also calculated age-specific and adjusted cancer mortality
rates for selected sites per 10,000 in the exposed and nonexposed populations;
relative risks (RR) were then computed. Among males ages 40 to 64 years, and
80 years and above, intestinal cancer risks for the exposed were generally
equal to those of the nonexposed; however, risks among males 65 to 79 were
elevated (RR = 1.6, p > 0.05), based on chi-square with Yates correction factor
and 1 degree of freedom. Intestinal cancer risks appeared not to vary by geo-
graphic location or duration of employment.
The relative risk for lung cancer in males was significantly (p < 0.01)
elevated among those ages 40 to 64 (RR = 3.2) and 65 to 79 (RR = 1.9); these
risks appeared to be inversely related to age (RR for those in the 80+ age
group ~ 1.2). Excess risks, though not significant, were observed for males in
the age group 40 to 64 years in the Atlantic Provinces (RR = 1.9); the age
groups 40 to 64 years (RR = 2.2) and 65 to 79 years (RR = 2.1) in Ontario and
Quebec; and among the age groups 65 to 79 years (RR = 2.9) and 80 years and
above (RR = 7.0) in the Western Provinces.
The author also examined lung cancer mortality rates and relative risks
by duration of employment and age. The numbers of lung cancer deaths among the
nonexposed were few in the categories of 11 to 20 years' employment (observed =
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1), and 21 to 30 years' employment (observed = 4), making it difficult to ob-
serve an overall pattern. The age-adjusted relative risk was elevated (p >
0.05) for the three categories of duration of employment (11 to 20 years, RR
= 9.4; 21 to 30 years, RR = 1.6; 31+ years, RR ~ 1.7), but no dose-response
relationship was observed. The elevation in risk appeared limited to males
below the age of 80 years (i.e., ages 40 to 79).
No excess in risk for the exposed relative to the non-exposed was observed
for lymphatic and hematopoietic system cancers. Risks for the exposed popula-
tion relative to the nonexposed were not computed for the other cancer sites.
The author next compared the mortality experience of those employed in the
refinery operations (N = 4,515, 35,604.5 person-years of observation) to those
employed in the non-refinery operations. Expected numbers of deaths for the
refinery workers were calculated based on the mortality experience of the non-
refinery workers. Hanis reported information on job titles for these two
groups of workers. As part of this review, job titles were rereviewed by a
certified industrial hygienist to determine which job titles would have employ-
ees that were potentially exposed to gasoline. There were 17 job codes identi-
fied for the refinery population, nine of which were considered to have job
titles in which workers would have potential gasoline exposure: (1) gauger;
(2) operations, processing, field supervisors, dewaxing, asphalt stills, crude
stills, and clay press; (3) packaging and shipping; (4) mechanics, boiler-
makers, and pipe fitters; (5) chemists; (6) garage workers; (7) electricians;
(8) handymen and laborers; and (9) custodial services. There were 17 addition-
al job codes identified for the non-refinery population, only 5 of which were
considered to have job titles in which workers would have potential gasoline
exposure; (1) marketing, shipping, transportation, and filling; (2) marine
workers; (3) gaugers; (4) mechanics; and (5) chemists. Additional job titles
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Including numbers of workers in each job were not provided.
SMRs for refinery workers were generally similar to the results observed
for the exposed population. SMRs were significantly elevated for all causes
of death (SMR = 114, observed » 816, p < 0.01); all cancer deaths (SMR = 124,
observed = 164, p < 0.01); diseases of the respiratory system (SMR = 132,
observed * 54, p < 0.05); and for accidents, poisonings, and violent deaths
(SMR = 160, observed = 27, p < 0.05). Not observed among the exposed workers
but seen among this subcohort of refinery workers were elevated SMRs for
cancers of the intestines and rectum (SMR = 185, observed = 28, p < 0.01) and
other digestive organs (SMR = 181, observed =21, p < 0.01). A statistically
significant deficit was observed for malignant neoplasms of the lymphatic and
heraatopoietic systems (SMR = 47, observed - 7, p < O.OS). Statistically non-
significant elevations in the SMRs were observed for cancers of the prostate
(SMR - 138) and the urinary bladder and kidney (SMR «* 120).
Mortality rates and relative risks for the refinery workers by geographic
region were also calculated for cancers of the intestine and rectum, other di-
gestive organs, lung, and lymphatic and hematopoietic system. The age-adjusted
relative risk for intestinal and rectal cancer was significant (p < 0.05) at
2.0 for refinery workers as compared to non-refinery workers. A negative trend
was associated with age (ages 40 to 64, RR = 2.4; ages 65 to 79, RR = 2.0;
ages 80+, RR - 1.4). Risk for other digestive organ cancer was elevated signi-
ficantly (p < 0.05) for males in age group 65 to 79 years (RR = 10.3); however,
among workers in age groups 40 to 64 years and 80 years and above, no risk was
apparent (RR = 1.1 and RR 1.0, respectively). Duration of employment also
appeared to be inversely related, at least for the categories of employment
presented, to the risk of cancer of the intestine and other digestive organs
(11 to 20 years, RR = 17.5, p < 0.01; 21 to 30 years, RR = 2.5, p > 0.05; 31+
4-42
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years, RR = 1,2, p > 0.05), The age-adjusted relative risk for total intes-
tinal and other digestive organ cancer (ICD 153-159) was elevated among refin-
ery workers in each of the geographic areas that had observations (Area 1, RR
- 2.2; Area 2, RR = 1.5; Area 3, RR = 2.7), though none was significantly ele-
vated. A significant (p < 0.05) risk was observed among refinery workers ages
65 to 79 in the Ontario and Quebec Provinces (RR = 4.8). A much smaller In-
crease in risk (RR = 1.3, p > 0.05) was observed for males in the age group 40
to 64 years in the area. Risks were also elevated at nonsignificant levels for
males in the age groups 40 to 64 years (RR - 3.9) and 80 years and above (RR =
3.1) in the Western Provinces. No increase in risk was observed for refinery
workers in the age group 65 to 79 years in the western area; however, the num-
ber of observed deaths was small.
Lung cancer risks were not significantly elevated among the refinery work-
ers, a pattern very different from what was observed among the exposed workers
(age-adjusted RR among refinery workers as compared to non-refinery workers -
1.18, p > 0.05; age-adjusted RR among exposed workers against nonexposed = 2.3,
p < 0.01). The risk among the refinery population in comparison to the non-
refinery population was lower than expected for lymphatic and hematopoietie
system cancers (age-adjusted RR = 0.46, p > 0.05).
Lastly, the author calculated SMRs by selective job titles for cancers of
the intestine and rectum, other digestive organs, lung, and lymphatic and hema-
topoietie system. As part of this review, these job titles were rereviewed by
a certified industrial hygienist to identify those job titles that would have
employees with potential gasoline exposure. Four gasoline exposure categories
were thus Identified: (1) mechanics, bollermakers, and pipefitters (N = 1496);
(2) operations, processing, field supervisors, dewaxing, asphalt stills, crude
stills, and clay press (N = 1303); (3) marketing plant and clerks (N = 609);
4-43
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and (4) packaging and shipping (N = 494).
In general, SMRs for workers for selected cancers in the four gasoline
exposure categories were observed to be in excess, though not at significant
levels (a,= 0.05), even though the numbers of observed deaths were small.
Specifically, the SMR for workers in the mechanics category was elevated for
cancer of the intestine and rectum (SMR = 167.8) as well as for cancer of the
other digestive organs (SMR = 134). The SMR for males in the operations cate-
gory was in excess for lymphatic and hematopoietic system cancers (SMR = 127.7)
only. Risks among the marketing plant employees were elevated for both lung
cancer (SMR = 166.2) and lymphatic and hematopoietic system cancer (SMR =
131.8). Packaging and shipping workers exhibited an elevated risk of lymphatic
and hematopoietic system cancers (SMR = 230) only.
Five job title categories were considered to have employees that would not
be exposed to gasoline. A statistically signficant (p < 0.05) excess was ob-
served among engineers (N = 625) for other digestive organ cancer (excludes
intestinal and rectal cancer) (SMR = 357.5, observed = 4). Though elevated,
SMRs were not significant for intestinal and rectal cancer among males in the
services, i.e., laundry, custodial, watchmen, and inspectors (N = 156, SMR =
293.8); lung cancer among garage workers and route salesmen (N = 807, SMR =
146.0); or for lung cancer among males employed in the utilities, building
trades, or boilerhouse (N = 226, SMR = 200.4). No excess in risk was observed
among the office workers (N = 2546).
This study provides insufficient evidence with which to associate employ-
ment in the petroleum industry with cancer risk. Gasoline exposure information
was not available. Job titles, a proxy measure of gasoline exposure, were pro-
vided, but results of these analyses were inconsistent. The only significant
cancer finding by job title was for digestive system cancers, excluding those
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of the intestine and rectum, for a job considered not to have potential expo-
sure to gasoline (i.e., engineers).
There are other limitations to this study. There was no control for con-
founding variables such as other chemical exposures (e.g., asbestos and the
pipe fitters) and smoking. A major limitation is that all employees who ter-
minated employment prior to being vested in the pension plan were excluded from
the cohort (6,681) or were lost to follow-up (865). This has probably led to
an underreporting of mortality for Imperial Oil Company employees. Mortality
may also have been underreported for employees who were vested in the pension
plan but who terminated or retired early, since the company made no attempt to
contact these individuals or verify their vital status until they reached pen-
sion age. Company records were the only source of vital status ascertainment;
therefore, mortality may be underreported for the total cohort. Thus, the
estimate of risk for this cohort may be underestimated.
The period of follow-up was short, only 10 years. This is especially
important because approximately half of the cohort was under the age of 50 at
the time of last observation. Thus, this study provides insufficient evidence
of an association between employment in the petroleum industry and a risk of
cancer.
4.2.1.3. Hanis et al. (1979)—Hanis et al. (1979) conducted a mortality study
of the employees of Imperial Oil Company, Ltd. of Canada and collected informa-
tion on 21,732 male employees who were either actively working or who were
annuitants during the 10-year observation period of 1964-73.
This study population is generally the same population as previously
reported on by Hanis (1977); however, the methods of analyses differ.
Data were obtained on current age, years of service with the company,
employment status (active, retired, terminated, or dead), date of retirement,
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date of death, cause of death, and job title, function, and location. Based on
the Information regarding the latter, employees were classified by exposure as
well as by refinery work. The exposure classification was as follows:
1. Exposed - person who had daily occupational contact with petroleum or
Its products.
2. Moderately exposed - person who had less than daily contact with
petroleum or its products (it could be as much as 2 weeks every month).
3. Non-exposed - person who had no known occupational contact with petro-
leum or its products.
About 1.6% of the total employees were exposed to petroleum or its products
only for a short period of time. If the exposure was for more than 5 years,
the employees were included in the exposed group; if the exposure was for less
than 5 years, they were included in the non-exposed group.
The classification of refinery work was based on the location of the job,
as follows:
1. Refinery work - person who worked daily on a refinery site irrespec-
tive of exposure to petroleum.
2. Non-refinery work - person who worked at sites other than refinery.
The final study population was obtained by the exclusion of females,
summer students, short-term employees (with less than 5 years' service with the
company), employees actively working during the study period but who had had
less than 1 full year of employment, 19 retired employees who had died during
the study period and on whom no information was available, and 865 employees
who were lost to follow-up.
The verification of underlying cause of death was achieved with the help
of Provincial Registrars (except for one province) and Statistics Canada, Of
a total of 1,511 deaths during the study period, information was not available
4-46
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for 1.6% of the decedents.
A total of 82,057.0 person-years of observation was contributed by 15,032
Individuals, Age-adjusted, cause-specific mortality rates were calculated by
using the direct method of age adjustment with the total population as the
reference population. This study presented the analyses of cancer deaths.
Analyses were carried out by exposure group and refinery group in three geo-
graphic locations: the Atlantic provinces, Ontario/Quebec, and the western
provinces. Of 301 cancer deaths, 5 deaths were in the less than 40-year age
group; hence this group was omitted from the detailed analyses.
Analysis by exposure group revealed that there was statistically signifi-
cant (p < 0.05) excess mortality in the exposed group from all cancer (RR =
1.23), cancer of the esophagus and stomach (RR = 3.25), and cancer of the
trachea, bronchus, and lung (RR = 1.89) as compared to the non-exposed group.
For the moderately exposed group, the mortality risk for total cancer and site-
specific cancers appeared to be less than that for the non-exposed group. As
pointed out by the authors, this was probably due to the very small number in
this group.
The same pattern was observed for both cancers of the esophagus and stom-
ach, .and of the trachea, bronchus, and lung, when geographic locations were
taken into consideration. Although none of the RRs was statistically signifi-
cant, the RRs were increased among the exposed group for cancer of the esophagus
and stomach in Ontario/Quebec and the Western Provinces when compared to the
non-exposed group. Exposed/non-exposed group comparison for cancer of the
trachea, bronchus, and lung showed Increased RRs for the same two geographic
locations. This cancer risk appears to increase geometrically from eastern to
western Canada.
Mortality rates by length of employment demonstrated positive trends with
4-47
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Increasing duration of employment both for cancers of the stomach and esopha-
gus, and of the lung, trachea, and bronchus, Indicating a dose-response rela-
tionship.
The refinery group showed a higher risk for mortality from cancers of all
sites, intestine and rectum, and other digestive organs when compared to the
non-refinery group. The RRs were 1.29, 1.97, and 1.82 (p < 0.05 for all the
RRs), respectively.
Although analysis by geographic location showed that there was a higher
risk for cancers of the intestine and other digestive organs in the respective
regions for refinery workers as compared to non-refinery workers, any meaningful
Interpretation is difficult due to the small numbers in the Atlantic and Western
Provinces.
Analysis by length of employment in the refinery classification did not
show any trends with increasing length of employment either for cancer of the
intestine and rectum or for cancer of other digestive organs.
When data were examined by specific subgroups of exposure in refinery and
non-refinery settings, higher mortality rates were observed for cancer of the
esophagus and stomach in refinery/exposed, refinery/moderately exposed, non-
refinery/exposed, and non-refinery/moderately exposed, as compared to non-
exposed in their respective refinery/non-refinery settings. Similar findings
were not evident in these groups for cancers of the intestine and rectum,
other digestive organs, and trachea, bronchus, and lung. Most of these rates,
except for the refinery-exposed groups, were based on very small numbers.
Analysis by various job titles for the same four above-mentioned cancers
produced mixed results but does show some increased risk. However, these
rates are based on extremely small numbers and hence are not reported here in
detail.
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This mortality study was conducted on a large population (15,032) and had
a total of 82,057 person-years of observation. However, the follow-up period
was fairly short. Age-adjusted mortality rates were used for the analyses,
which makes it difficult to compare this study with other studies. The total
study population of the work force was used as a standard population for direct
age adjustment, which may underestimate some of the risks 1f there 1s a common
exposure for this population that causes certain types of cancer. Analyses by
location and exposure, however, point toward cancers of the esophagus and
stomach, and trachea, bronchus, and lung. Other confounding factors, e.g.,
smoking and other occupational exposures, were not considered. Due to the
extremely small numbers, mortality rates by job categories do not provide much
help. Most important, specific exposure histories to gasoline were not presen-
ted.
In addition, in a letter to the editor, Schottenfeld et al. (1980)
question: (1) the use of an exposure classification criterion that does not
consider average dose level, duration, and uniformity of exposure over time;
(2) Hanis et al.'s assumption that exposure within 5-year age groups is homoge-
neous within a particular cohort; Schottenfeld et al. suggest that the authors
should have used the Mantel-Haenszel procedure (Mantel and Haenszel, 1959) as
a summary measure of relative risk rather than make such an assumption; (3) the
combining of esophageal epidermoid carcinoma and stomach adenocarcinoma Into a
single cause-of-death category, since each has a different etiology; (4) the
authors' failure to use a test of linear trend to test for dose-responses;
and (5) that the lung cancer excess reported by Hanis et al. may reflect an
occupational association other than with petroleum products (e.g., asbestos);
Schottenfeld et al. suggest that smoking Information be acquired on the cohort
members.
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Hence, this study Is considered inadequate to use as a basis for drawing
any conclusions with regard to gasoline exposure.
4.2.1.4. Therl.auIt and Goulet (1979)—The Investigators conducted a retrospec-
tive mortality study of 1,205 males (race not specified) who worked at a Cana-
dian oil refinery plant for more than 5 years between 1928 (the start of plant
operations} and December 31, 1975. Vital status was determined as of December
31, 1976.
The company furnished personnel information on each person, including
name, date of birth, date of employment, work termination date, last known
address, social insurance and employment insurance numbers, and a classifica-
tion of workers according to the type of work; i.e., operation, maintenance,
or office work. Males who terminated employment were traced through several
means including telephone calls, the Motor Vehicle Bureau, the Quebec Health
Insurance Board, the Pension Board, the Unemployment Insurance Commission, the
Quebec Population Registry, and letters to fellow workers. Lost to follow-up
were 190 males (16% of the original study population) whose survival status
could not be ascertained. Thus the final study population consisted of 1,015
males, representing 17,545.6 person-years of observation.
Cause of death, as reported on the death certificate, was receded to the
8th revision of the ICD.
The SMRs were calculated using the age- and cause-specific death rates for
the Province of Quebec as the standard. Expected numbers of deaths for the
years 1928-62 were calculated using the 1951 rates, while the 1971 rates were
used for the years 1963-76. To test the differences between the observed and
the expected numbers of deaths, the Bailer-Ederer test (1964) for the ratio of
a Poisson variable to its expectation was used. For purposes of analysis, the
cohort was divided Into two subgroups: those with more than 20 years' and
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those with less than 20 years' time between the date of employment and time o"f
death. The SMRs for the combined subgroups were also calculated. Reported by
the authors but not reviewed here are nonsignificant cancer excesses based on
only one or two observed deaths.
There were 108 deaths observed; 91% occurred among employees who were 40+
years of age. The age distribution of the lost-to-follow-up group was similar
to those who were alive at the time of ascertainment.
The SMR for all causes of death among the combined cohort and among those
with less than 20 years of exposure was significantly reduced (p < 0.05) (SMR =
78, observed = 108 and SMR ** 63, observed « 33t respectively). Also reduced,
although not significantly, was the SMR for all causes of death among those
with 20+ years of exposure (SMR = 88). The SMRs for total cancer mortality
among the total cohort were also lower than unity (SMR = 89, observed = 25,
p < 0.05). Similar patterns were observed among the two exposure groups. The
SMR for malignant neoplasms of the brain/CNS for those exposed less than 20
years was significantly elevated at 652 (observed = 3). The only other signi-
ficant SMR (17, observed = 1) was observed among those with 20+ years of expo-
sure whose cause of death was accidents and violence.
SMRs were elevated, though not significantly, for malignant neoplasms of
the male genital organs/bladder/kidney (SMR = 152), and of the digestive system
(SMR - 126) among those with 20 or more years of exposure. Similar patterns
were observed among the total cohort, but the SMRs were smaller. Also eleva-
ted (p < 0.05) was the SMR for diseases of the digestive system (SMR = 179,
observed = 7) among those with 20 or more years of exposure.
Job titles for the 25 cancer deaths were reported by the authors: 4 were
in operations, 4 were office employees, 11 were maintenance workers, and 6
belonged to more than one group. Except for the office workers, all of the
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workers may have been exposed to gasoline.
These results provide Insufficient evidence for the carcinogenic poten-
tial of gasoline vapors. Gasoline exposure information was not presented.
The refinery also operated a laboratory, and confounding variables, such as
exposure to other chemicals, were not controlled for.
One hundred and ninety (16%) males were totally eliminated from the
study population because they were lost to follow-up (rather than including
these subjects in the study population until the point of loss). As a result,
the expected numbers of deaths may be artificially low (Monson, 1980), thus
potentially overestimating the SMR.
The authors' use of the 1951 age- and cause-specific death rates as the
standard population for the period 1928-62 is questionable, since mortality
rates have greatly changed over this period of time.
Finally, confounding factors such as smoking were not taken into con-
sideration. Thus, these data provide insufficient information with which to
assess an association between gasoline vapors and cancer.
4.2.1.5. Thomas et al. (1980)—Thomas et al. (1980) conducted a proportion-
ate mortality study of decedents who at the time of their deaths were active
members of the Oil, Chemical, and Atomic Workers International Union (OCAW).
The deaths were reported to OCAW International Headquarters by the union's
locals in Texas between 1947 and 1977. Of the total number of deaths that were
reported, death certificates could not be located for 10%, and these were not
included in the study. Of the 3,105 decedents for whom there were death certi-
ficates, about 40% were less than 50 years of age at death; about 40% were
union members for less than 10 years, and 25% were union members for 20+ years.
The individual plants in which the members had worked were classified into
one of five major categories, according to major Industrial process. Of the
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3,105 deaths, 67.2% were classified in the petroleum refining and production of
petrochemicals category. Since this category was considered by the reviewers
to be the most relevant of the categories to an assessment of gasoline expo-
sure, the results of this category alone are discussed here.
The underlying cause of death was coded by a trained nosologist in
accordance with the 8th revision of the ICD. Information on age at death,
race, and cause of death was combined with data obtained from the union to
formulate a final record on each subject.
The expected number of deaths was calculated by applying the race- and
cause-specific relative frequencies of death among U.S. males to the total
number of deaths in the study group, with appropriate adjustments for age and
calendar year. Proportionate mortality ratios were calculated for various
cancer sites by dividing the observed number of deaths from a particular can-
cer by the expected number. For each cancer site with an elevated PMR, Texas
Proportionate Mortality Ratios (TPMRs) and Proportionate Cancer Mortality
Ratios (PCMRs) were calculated using the relative frequencies for Texas males
and the proportionate cancer mortality for U.S. males, respectively. Statis-
tical significance was determined by use of the summary chi-square test.
The PMR for all cancer deaths was elevated for white (PMR = 126, observed
= 394, p < 0.01) and non-white (PMR = 127, observed = 79, p > 0.01) Workers.
A PMR excess (p < 0.01) was also observed for arteriosclerotic heart disease
for both racial groups (white, PMR = 119, observed = 687; non-white, PMR = 149,
observed = 114). However, statistically significant deficits (p < 0.01) were
observed among whites only for respiratory diseases (PMR = 36, observed = 27)
and digestive diseases (PMR = 65, observed = 68). Non-white males had sig-
nificantly elevated (p < 0.01) PMRs for motor vehicle accidents (PMR = 184,
observed = 29) and a significantly greater PMR was observed for non-motor
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vehicle accidents for whites only (PMR = 154, observed = 145, p < 0.01).
The cause-specific cancer PMRs showed significant (p < 0.05) excesses for
whites, for the digestive organs and peritoneum (PMR = 124, observed = 111),
respiratory system (PMR = 131, observed = 134), brain and CNS (PMR = 176,
observed * 25), and skin (PMR » 194, observed = 14). Similar excesses were
observed for non-whites, for cancers of the respiratory system (PMR - 139) and
digestive system (PMR = 138), but these excesses were not statistically sig-
nificant.
Analysis by length of union membership revealed PMR excesses for cancer of
the stomach (PMR = 269, observed = 14, p < 0.05) and cancer of the kidney (PMR
- 214, observed = 7, p < 0.05), both in the 20+ years' membership group in
white males. In the same group, the TPMRs were also significant^for both of
these causes (TPMR = 278 and 251, respectively). The only other statistically
significant elevation of the TPMR was observed in white males for cancer of the
brain and CNS (TPMR = 245, observed = 12, p < 0.05) in the 10 to 19 years'
membership group. A similar analysis for non-white males revealed a PMR excess
for stomach cancer (PMR = 280, observed = 12, p < 0.05) in the 10+ years'
membership group. The corresponding PCMR was 192 and the TPMR was 259 for this
cause in this group, and both were significant at the 0.05 level, while the PMR
was 242 (observed = 5, p < 0.05) for the non-white group with union membership
of less than 10 years. However, the corresponding TPMR and PCMR were not sig-
nificant.
These results provide very weak evidence for the carcinogenicity of gas-
oline vapors because of several study limitations. Death certificates were
not available for 10% of the population, i.e., for about 350 deaths. This may
lead to underreporting of certain causes of death and may heavily influence the
cause-specific mortality frequencies, especially if the underreporting occurred
4-54
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for specific causes where the numbers were small to start with. This limita-
tion was also expressed by Wong and Tabershaw (1980) 'in their letter to the
editor. '
Since the study was limited to active members of the union, thereby ex-
cluding union members who had retired or left for other reasons as well as
non-union members, the results may overrepresent diseases with very low sur-
vival rates and underrepresent diseases that tend to occur in retirees, or to
have a longer latency period. These concerns were also expressed by Wong and
Tabershaw (1980) and Divine (1980).
A serious inherent problem with this study is 1n the usefulness of the PMR
statistic. In addition, exposure Information on gasoline was not available.
Confounding variables such as other chemical exposures and smoking were not
taken into consideration.
There is another question with regard to the adequacy of the latency
period used in this study. A surrogate measure of latency is length of union
membership. Approximately 4Qf and 25% of the decedents were OCAW members for
less than 10 years and more than 20 years, respectively. Thus, for a signifi-
cantly large population, the period between first exposure and death was less
than the generally accepted average latency period of 10 to 30 years for envi-
ronmentally induced cancers.
Thus, this study provides very limited evidence of an association between
gasoline and cancer risk.
4.2.1.6. Wen et al. (1981, 1982, 1983, 1984a)--This is a retrospective cohort
study of all regular employees who worked at a Gulf Oil refinery located in
Port Arthur, Texas. The refinery was a full service operation involved in re-
fining crude oil and manufacturing fuels, oils, lubricants, and petrochemicals
such as benzene, cumene, ethylene, and cyclohexane. Vinyl chloride was never
4-55;
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manufactured at the refinery. The authors examined mortality extending over a
period of 41 to 44 years and presented analyses of the data in four papers. No
information was provided by the authors as to why the period of study differed
for the four analyses. Described here are the authors' methods of cohort
selection and data collection; the authors* results are reviewed separately.
The cohort consisted of all regular employees who worked at the refinery
between January 1, 1937, and January 1, 1978, in the study covering the short-
est time Interval (Wen et al., 1983, 1984a)» and between June 15, 1935, and
December 31, 1979, in the study covering the longest time interval (Wen et al.,
1982), regardless of length of employment. Demographic and work histories were
obtained from the company's personnel records. Verification and supplementa-
tion of information was done by using other corporate records such as annuitant
insurance, seniority lists, and medical and mortality records. Records Includ-
ed vital information on date of hire, date of retirement or termination, pay
status, and, if deceased, date of death. Pay status was classified as salaried
or hourly, depending on the percentage of time worked in each category. Vital
status was determined by tracing through the SSA, the Texas and Louisiana
Departments of Motor Vehicles, and local telephone directories, followed up by
inquiries made to former employees, friends, relatives, and neighbors.
Death certificates were obtained either from the company's personnel, ben-
efit, or medical records, or from the various states' vital statistics depart-
ments. The underlying causes of death were coded by a trained nosologist ac-
cording to the 8th revision of the ICD. Person-years at risk were calculated
from the beginning of the follow-up period or from the date of employment,
whichever was later. Those lost to follow-up were calculated in the person-
years of observation up to the point of last known contact, usually employment
termination. SMRs were computed by using age-, sex-, race-, year-, and cause-
4-56
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specific mortality rates of the general U.S. population {Monson, 1974).
Significance testing was done by using the Polsson distribution (Wen et al.,
1981, 1983, 1984a) or a summary chi-square test with one degree of freedom {Wen
et al., 1982). Characteristics of the cohort analyzed for each of the four
papers are presented in Table 4-2. No information was provided by the authors
as to why the total numbers of deaths or those lost to follow-up were not
identical for the four analyses.
4.2.1.6.1. Wen et al. (1982). These analyses were originally presented In
1980 at the New York Academy of Sciences Workshop on brain tumors in the chem-
ical industry and subsequently published in 1982; they are therefore presented
here before the authors' 1981 analyses.
Analyses were restricted to the 15,698 male employees because of the small
numbers of females (1,823). White males represented 83% of the study popula-
tion, 316,574 person-years of observation; non-white males contributed 58,971
person-years of observation. Race was not known for 2.5% of the males, but
these were assumed to be white. Lost to follow-up were 9.8% of the white males
and 13.5% of the non-white males.
Approximately 40% of the males worked 20 years or more, 50% were employed
less than 9 years, and 70% were hired before 1950. This pattern was observed
for both race groups.
There were 4,660 observed deaths, and death certificates were not obtained
for 9% of these; a breakdown by race was not reported.
The SMR for all causes of death among all males was 89. A similar pattern
was observed stratifying by race (white SMR = 92, non-white SMR = 81). These
risks were not significant (p > 0.05). Risks for all malignant neoplasms were
equal to those of the U.S. population for both races (white SMR = 99, non-white
SMR = 110).
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fABLB 4-2. SUMMARX OF COHORT CHARACTERISTICS FROM FOUR WEN Bf AL. STUDIES
Wen ot al, (1981) Wen *t al. (1962)* Wen *t al. (1983) Wen *t al. (19848)
ParJod of follow-up 6/15/35—1/1/78
T!m* of employment 1 day
required for
Inclusion
Number of years of
observation
42.5
6/15/35—12/31/79
I day
44.5
1/1/37—1/1/78 1/1/37—1/1/78
I day I day
41.0
* Originally presented in I960, subsequentIy published in 1982.
b NR • Not reported.
c Values In parentheses represent percent of total.
41.0
Number of persons 17,350
followed (total)
Number of person-years 406,659
observed (total)
Number of white males 12,960
followed
Number of person-years 315,167
observed (white males)
Average length of 23.4
follow -op (years)
Number lost to follow- 2,185 (I3*)c
up (total)
Number lost to follow- 1,216 (9.81)
up (white males)
Number of deaths 4,434
(total)
Number of observed 3,494
deaths (white males)
Death certificates 299 (8.6%)
unascertained
(white males)
17,521 16,880 16,880
408,073 406,198 406,198
13,074 12,526 12,526
316,574 313,067 313,188
NR° 24.1 NR
2,278 (13*) 1,542 (9. If) NR
1,281 (9.8*) 727 (5.8*) 730 (5.8*)
4,766 4,361 4,358
3,753 3,444 3,441
9% 218 (6.3*) NR
(all males)
4-58
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Analyses by specific cause of death were only presented for brain tumors.
None of the SMRs reported was statistically significant. The SMR among white
males for malignant brain tumors was 85; the SMR equaled 108 for benign or un-
specified brain tumors. SMRs were not reported for the non-whites because of
the small numbers of observed deaths (observed malignant = 3, observed benign
-oV unspecified =2); however, the SMRs can be calculated (Fleiss, 1981) as 150
for brain cancer and 133 for benign or unspecified brain tumors (p > 0.05).
SMRs for brain tumors in males by length of employment (less than or
greater than 20 years) were calculated stratifying by race and diagnoses, (ma-
lignant or benign). None of the SMRs was statistically significant. The data
suggest that risks for white males employed less than 20 years at the refinery
were less than for the U.S. population (SMR = 65), but that among white males
employed 20 or more years, malignant brain tumor risks may be slightly eleva-
ted, although not significantly, over U.S. risks (SMR = 109). Risks for benign
brain tumors among white males employed at least 20 years were 80% greater than
for the U.S. population (SMR = 184). Risks for non-white males were not
reported; however, they can be calculated as 93 for brain cancer among those
employed less than 20 years (observed = 1) and 217 (observed = 2) among those
employed more than 20 years. Risks for benign brain tumors were also elevated
(SMR = 317, observed = 2) among those employed 20 or more years (p > 0.05).
This study presents insufficient data to assess the association of gaso-
line with brain cancer. No quantitative measures of gasoline were available.
Details on job assignments and proxy measures for exposure were not reported.
The refinery manufactured petrochemicals (e.g., benzene) as well as gasoline,
and exposures to these other substances were not controlled for.
The cohort of 15,698 was followed for 44 years. Considering this fact,
the tracing of vital status was very good, and tracing procedures were very
4-59
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thorough, although one could question using SSA records before 1946, since SSA
records for mortality follow-up were not very complete until after World War
II, and hence their use may lead to an understatement of deaths„ If a DMV
license had been issued through 1980, the person was assumed to be alive, which
may also lead to some understatement of mortality. Anyone who ever worked at
the refinery during the study period was included in the cohort, which may lead
to the inclusion of persons with little or no exposure in the denominator and
hence to underestimation of risk.
The authors report analyses of brain tumor deaths by age at death, year
of hire, length of employment, and year of death; however, these analyses did
not post-stratify by race or brain tumor diagnosis (i.e., malignant or benign).
Another criticism of this study is that both white- and blue-collar work-
ers were included in the cohort, and analysis failed to control for this fact;
thus, risks for those involved in manufacturing of petroleum products (i.e.,
blue-collar workers) may be underestimated.
Finally, the brain is a common site of metastasis, and without knowing if
the brain cancer is primary, it is not possible to draw conclusions of an
association between brain cancer and employment in the petroleum refining
industry.
4.2.1.6.2. Wen et al. (1981). This study reports detailed analyses of the
brain tumor data previously presented in 1980 by the authors (Wen et al.,
1982). The length of this study was 2 years shorter (June 15, 1935 to January
1, 1978) than previously reported. The cohort of 17,350 workers consisted of
15,556 (90%) males, 83% white and 17% non-white, and 1,794 (10%) females. Lost
to follow-up were 1,551 (10%) of the males and 634 (35%) of the females. Thus,
analyses were limited to males only (374,202 person-years of observation).
The distribution of male workers by race, time of hire, and length of
4-60
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employment was similar to that reported in the previous study. Also included
were details on pay status, classified as salary OP hourly depending on the
percent of the work in each category. These data indicated that 82% of the
white males and 98% of the non-white males never worked as salaried employees.
Similar patterns of risk were observed to those previously reported for
all causes of death, except that risks were reported at significant levels
(p < 0.01); among white males the SMR equaled 88 (observed = 3,494), and among
non-white males the SMR equaled 75 (observed = 842). Risks for all malignant
neoplasms were slightly lower than those originally reported but were not sig-
nificantly reduced (white SMR = 94; non-white SMR = 93). Brain cancer risks
for white males were also lower (SMR = 76) than previously reported (SMR = 85).
Brain tumor mortalities were further examined by pay status; hourly employ-
ees were those with 100% of their employment on an hourly basis, and salaried
employees were those with 75% of their employment on a salaried basis. Risks
for salaried employees were slightly lower than risks for hourly employees,
regardless of race or cause of death (i.e., all causes, all cancers, and brain
tumors).
To further evaluate the effect of the lost-to-follow-up group, a subcohort
was selected. Referred to as the 1940 cohort, this subcohort consisted of em-
ployees hired on or after January 1, 1940, with a minimum of 6 months of employ-
ment. Lost to follow-up were only 3.8% of the white males and 6.5% of the non-
white males. The final 1940 cohort of 11,526 males represented 275,785 person-
years of observation. Similar patterns of risk were observed (p > 0.05); the
SMR for white males for brain cancer was observed at 66. The SMR for non-whites
was not reported but can be calculated as 189.
This study has many of the same limitations as the previous study. Gaso-
line exposure could not be assessed. Details on job titles were not available.
4-61
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Confounding factors were not controlled for.
The authors did attempt to correct a limitation of the previous study by
Including analyses by pay status, using hourly employees as the proxy measure
for blue-collar workers; however, results were only presented for all brain
tumors. No analysis was presented for malignant brain tumors by pay status.
Analyses of all brain tumor risks by latency and length of employment were
presented, but no analyses of these important factors were presented for malig-
nant brain tumors.
Finally, the authors presented no rationale for why this study period was
shortened by 2 years from what was originally reported, thus excluding two of
the white male brain cancer deaths from the study population.
Thus, this study provides insufficient data to assess the association
between gasoline and primary brain cancer in males.
4.2.1.6.3. Wen et al. (1983). This study analyzes the previously reported
(Wen et al., 1981, 1982) Port Arthur, Texas, cohort for all causes of death.
This period of study began 1-1/2 years later and ended 2 years sooner (January
1, 1937 to January 1, 1978) than what was initially reported by the authors in
1980 (Wen et al., 1982). No explanation was provided by the authors as to why
the period of study differed.
In this study, 16,880 employees were included in the cohort, of whom
15,095 (89.4%) were males contributing 372,505 person-years. The follow-up
was successful for 94% of the males and 68% of the females; however, this study
presented findings for males only. Of 4,269 male deaths, death certificates
were located for 3,982 (93.3%). As in the other Wen et al. (1981, 1982)
studies, 70% of the male cohort began work prior to 1950; approximately 40%
worked for 20 or more years.
SMRs for all causes of death and all cancers were 84 (observed =4,269,
4-62
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p < 0.01) and 96 (observed = 839, p > 0.05)9 respectively. Both showed defi-
/
cits, confirming the popular belief in the "healthy worker" effect. The total
cohort showed more statistically significant (p < 0.05) deficits than excesses,
including deficits for cancers of the digestive organs (SMR = 82, observed =
231), esophagus (SMR =44, observed = 12), rectum (SMR = 60, observed = 19),
liver (SMR = 35, observed = 8), and bladder (SMR = 46, observed =13); lympho-
and reticulosarcomas (SMR = 24, observed = 4); and diseases of the circulatory
system (SMR = 79, observed = 2,036), respiratory system (SMR = 68, observed =
203), gastrointestinal system (SMR = 59, observed = 75), and infective and
parasitic diseases (SMR = 35, observed = 60). The only significant SMR eleva-
tion was for cancer of the bone (SMR = 205, observed = 11, p < 0.05). Cancer
of the eye had an SMR of 286, based on only two deaths. Hodgkin's disease had
an SMR of 145 and cancer of the skin had an SMR of 122, both based on 16 ob-
served deaths. All of the other SMRs were less than 120, none being statisti-
cally significant.
Analyses of the cohort by pay status revealed deficits for all causes of
death (SMR = 67, observed = 300, p < 0.01) and all cancers (SMR = 79, observed
= 61, p > 0.05) in salaried workers (white and non-white; this pay group com-
prised 11% of the total population). All other cause-specific mortalities also
showed deficits. When cancer mortality was examined in this group, two excesses
were observed; these were for cancer of the pancreas (SMR =189) and cancer of
the skin (SMR = 140), based on eight and two deaths, respectively. Both of
these SMRs were statistically nonsignificant. A statistically significant
cancer deficit was observed for stomach cancer (SMR = 17, observed =1) for
this subcohort.
Both white and non-white hourly workers had SMR deficits for all causes of
death. The SMRs for workers in this pay group were 90 (observed - 3,146) and
4-63
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73 (observed = 823), respectively, both being statistically significant (p <
v
0.01) deficits. These same groups also had SMRs of 99 and 92, respectively,
for all cancers, neither being statistically significant; the SMR for diabetes
mellitus was elevated, but not significantly (SMR = 112) in the non-white group
only. SMR deficits were seen for all other causes. Among white hourly workers,
a significant cancer deficit was observed for cancers of the esophagus (SMR =
47, observed ~ 7), liver (SMR = 46, observed = 7), and bladder (SMR = 47,
observed - 10), and for lympho- and, reticulosarcomas (SMR - 8, observed = 1).
Both racial groups had a higher mortality for bone cancer, with SMRs of 228
and 217 for whites and non-whites, respectively (p < 0.05). These excesses
were based on nine and two deaths, respectively. Whites also showed an in-
crease in the SMR for eye cancer (SMR = 341), based on two deaths, and skin
cancer (SMR » 122), based on 13 deaths. All other SMR increases were under
120 and were statistically nonsignificant. When this group was analyzed
according to those who had worked 1 year or more, similar excesses in bone
cancer SMRs were observed in both races; among whites the SMR equaled 275 (nine
deaths), and among non-whites the SMR equaled 245 (two deaths). Both were
statistically nonsignificant.
This study has the same limitations as the previous Wen et al. (1981,
1982) analyses. Once again, neither exposure levels nor job titles were avail-
able. No analyses were performed either for latency or length of employment,
although for a cohort of this size with a 41-year observation period, this
would have been feasible.
The authors went to great lengths to calculate and show that the study had
an adequate statistical power in terms of detecting increases for the various
causes of cancer deaths studied, but in the absence of any occupational expo-
sure histories the study is inadequate to use as a basis upon which to draw any
4-64
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conclusions.
4.2.1.6.4. Wen et al. (1984a). These analyses examined the mortality experi-
ence of active, retired, and terminated workers. The period of study was the
same as the authors' 1983 study (January 1, 1937 to January 1, 1978); however,
these analyses were limited to white males only. Of a total of 12,526 white
male employees contributing to 313,188 person-years, 6,199 (contributing 41% of
the total person-years and 38% of the 3,441 deaths) had terminated, and 2,837
(contributing 8% of the person-years and 37% of the deaths) had retired by the
end of the study. The active group numbered 2,635 and contributed 51% of the
total person-years and 25% of the deaths. The mean age at death was 53 for
active, 57 for terminated, and 74 for retired workers.
The SMRs for all causes for active, terminated, and retired workers were
68 (observed = 855, p < 0.01), 104 (observed = 1,306, p > 0.05), and 89 (ob-
served = 1,280, p < 0.01), respectively. SMRs for all cancers for active, ter-
minated, and retired workers were 85 (observed = 177. p < 0.05), 98 (observed
= 234, p > 0.05), and 105 (observed = 270, p > 0.05), respectively.
There was no significant excess for any site-specific cancer cause of
death among any of the three groups. Reported by the authors but not reviewed
here are nonsignificant cancer excesses based on fewer than three deaths.
Nonsignificant increases among the active group were observed for cancers of
the pancreas (SMR = 146), kidney (SMR = 142), bone (SMR = 164), and for leu-
kemia (SMR = 155). Excesses (p > 0.05) were observed among the terminated
group for cancers of the buccal cavity and pharynx (SMR = 122), pancreas (SMR
= 113), lung (SMR =115), bone (SMR = 216), skin (SMR = 156), prostate (SMR =
130, and for Hodgkin's disease (SMR = 160); and among the retired group for
cancers of the lung (SMR = 118), bone (SMR = 246), skin, (SMR = 118), kidney
(SMR = 132), prostate (SMR = 114), brain (SMR = 117), and other lymphatic
4-65
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tissues (SMR = 159), and for leukemia (SMR - 158). Statistically significant
deficits were found for cancer of the lung (SMR = 67, observed = 38, p < 0.05)
in active workers and cancer of the liver and biliary passages (SMR - 16,
observed = 1, p < 0.05) in retired workers.
The authors divided the retired group into three subgroups for further
analyses: (1) employees who retired at 65 or later, i.e., regular retired;
(2) employees who retired early on the basis of a medical disability, i.e.,
disability retired; and (3) all employees who retired before 65 including
disability retired, i.e., early retired. The SMRs for all causes of death
among the regular and early retired were significantly (p < 0.05) lower than
for the U.S. white male population (SMR = 87, observed =246, and SMR =89,
observed = 485, respectively), while the SMR for the disability retired was
significantly (p < 0.01) higher (SMR = 164, observed = 53) for all causes of
death. The only other significant elevations in risk were for diseases of the
circulatory system for the disability retired (SMR = 154, observed = 27) and
diseases of the nervous system and sense organs for the disability retired
(SMR = 1300, observed « 3). Significant deficits were observed for all but
the latter diseases group among the early retired.
Borderline significant cancer risks were observed for regular retired
employees for skin cancer (SMR - 478, observed = 3, 95% CI 0.96-13.96).
Excessive nonsignificant cancer risks of 140 or above were observed among
each of the three retired groups. Among the regular retired employees, risks
were elevated for cancer of the kidney (SMR = 254), leukemia (ICD 204-207, 284)
(SMR - 183), and cancer of other lymphatic tissues (ICD 202, 203, 208) (SMR =
318). Among the early retired employees, risks were elevated for cancer of the
kidney (SMR = 154) and for leukemia (SMR = 144). Only one of the malignant
diseases had observations of three or more for the disability retired group;
4-66
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risk for this site was elevated (lung cancer, SMR = 150)
This study has some of the same limitations as the authors1 previous
analyses (Wen et a!., 1981, 1982, 1983). There is no information on gasoline
exposure or job titles, length of employment, or latency analysis. Additional-
ly, the authors failed to explain why this cohort of white males had three few-
er deaths than the same cohort reported in an earlier study (Wen et al.» 1983).
Risks for those involved in petroleum refining operations may be underestimated,
since approximately 29% of the workers at this plant are management or clerical
staff (Moure-Eraso and Itaya, 1985) and therefore not likely to be exposed to
petroleum products. The authors Indicate that 99% of the lost-to-follow-up
group were terminated employees, and therefore deaths for this group may be
underascertained and risks may be artificially low.
Thus, this study provides Insufficient information to assess the carcin-
ogenicity of gasoline.
4.2.1.7. Rushton and Alderson(1981a)—The Rushton and Alderson paper is a
mortality study of all male workers who had worked for at least 1 year between
January 1, 1950, and December 31, 1975, at any one of eight refineries in Great
Britain; the total number in this large cohort was 34,781 individuals, for a
total of 575,982 person-years of observation, and the mean follow-up was 16.6
years for each person.
Tracing was successful for over 99% of the cohort. It was achieved either
through social security records at Newcastle using National Insurance numbers
or through National Health Service Central Registers at Southport and Edinburgh
using National Health Service numbers.
Personal data were obtained on full name, date of birth, address, date of
joining, and last or present job. For leavers, the date and reason for leaving
were obtained. For dead individuals, the underlying cause of death and up to
4-67
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three causes contributing to the underlying cause of death were coded, using
the appropriate revision of the ICD. Date of entry to the study was January 1,
1951, or 1 year after joining, whichever was later, depending on whether the
person was employed prior to or after January 1, 1950.
The SMRs were computed' by using 5-year age and calendar-period rates for
males in England and Wales for English and Welsh refineries and in Scotland for
Scottish refineries. Significance testing was done by the use of the Poisson
distribution.
The SMRs for all causes of death (SMR = 84, observed = 4,406), arterio-
s
sclerotic and degenerative heart disease (SMR = 90, observed = 1,428), and
tuberculosis of the respiratory system (SMR = 39, observed = 25) and bronchitis
(SMR = 64, observed = 253) showed statistically significant deficits (p <
0.0001). The only significant SMR elevation was observed for accidents that
were caused by fire and explosion (SMR = 201, observed = 12, p = 0.0196).
Although some statistically significant excesses were found for laborers for
various categories in different refineries, there was in general a lowered
mortality from nonmalignant causes in all the subgroups defined by job, age,
duration of service, etc.
SMR deficits were also observed for all cancer deaths (SMR = 89, observed
~ 1147, p s 0.0001) and for cancer of the lung and pleura (SMR = 78, observed =
416, p < 0.0001). Excesses were observed for cancer of the nasal cavities and
sinus (SMR = 224, observed = 7, p < 0.04) and for melanoma (SMR = 216, observed
^ 14, p < 0.007).
Analysis by job category revealed pronounced deficits for all cancer SMRs
in engineers, scientists, foremen, and administrative and clerical workers.
Other groups had an SMR of 100, with the exception of laborers (SMR = 111,
observed = 325, p < 0.05). A similar pattern was also observed for lung can-
- 4-68
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cer, except that the elevated SMR observed for laborers was not statistically
significant.
Detailed examination of data revealed excesses from cancer of the esopha-
gus, stomach, intestine, and rectum among workers from four of the eight refi-
neries. At one refinery there was a negative trend for stomach cancer with
increasing years of service, while the other demonstrated exactly the opposite,
a positive trend with increasing duration of service. A positive trend with
increasing length of service was observed in two refineries for cancer of the
intestine. Statistically significant SMR excesses were observed for the
following cancers: (1) cancer of the esophagus in operators in all refineries
together and in laborers in one refinery; (2) cancer of the stomach in laborers
in one refinery (this increase affected laborers, riggers, and fire and safety
workers); (3) cancer of the intestine for scientists from all the refineries
together and in one individual refinery, and for operators in another refinery;
and (4) cancer of the rectum in fitters from all of the refineries. This
increase was also observed in one refinery in fitters and operators.
All of the excesses were in age groups above 60 years, except for cancer
of the intestine, which occurred in the 45- to 59-year age group.
The significant increase in melanoma mortality basically came from two
refineries (11 of 14 deaths); of 5 deaths from one refinery, 4 were operators,
while the 6 deaths from the other refinery included two boilermakers, an opera-
tor, a pipefitter, a laborer, and a clerk. Fifty percent of these deaths were
in the under 45-year age group. In one refinery, an increased SMR was observed
for lymphosarcoma; although this was statistically significant, it was based on
very few numbers.
This study also has the same problem as the majority of the refinery
studies, i.e., lack of information on exposure to gasoline. Confounding vari-
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ables such as exposures to other chemicals, etc., are not taken into considera-
tion. Although the overall analysis showed increased cancer mortality of the
nasal cavities and sinus, no detailed analyses by age, latency, or length of
employment are presented. At one of the refineries, increases from cancers of
the larynx, prostate, and kidney and suprarenal are mentioned in the text, but
no details are provided.
The eight refineries studied here are of varying sizes and complexities
and may not deal with the same products. Some had chemical plants in addition
to oil refinery plants. Sometimes the mortality results of the different re-
fineries show exactly contradictory findings. For example, analysis by length
of service demonstrated that in one refinery, mortality from stomach cancer had
a negative trend with increasing duration of service, while another refinery
showed a positive trend in stomach cancer mortality with increasing duration of
service.
Although this study has a large sample size, more than adequate person-
years of observation, and a long follow-up, latency analyses were not carried
out. Because of the limitations discussed above, this study is considered
inadequate for drawing any conclusions with respect to cancer risk.
4.2.1.8. Schottenfeld et al. (1981)—Schottenfeld et al. (1981) reported the
results of a prospective mortality and morbidity study sponsored by the American
Petroleum Institute (API) and conducted by the Memorial Sloan-Kettering Cancer
Center (MSKCC). The study population consisted of full-time active petroleum
industry employees from 19 U.S. companies involved in petroleum refining,
petrochemical manufacturing, research and development, and quality control.
All reports of illness (more than 5 consecutive days), cancer incidence, and
mortality were to be collected. Annuitants of these companies also made up the
study population; however, since they were not actively employed, reports of
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illness or cancer Incidence were not routinely collected. This report presents
the results of mortality and cancer incidence only.
Results are reported for 76,336 white and Hispanic males who were employed
at any time between January 1, 1977, and December 31, 1979. This group com-
prises 87.3% of the entire study population and excludes females, blacks, and
races other than white or Hispanic. Only 18 employees (< 0.001%) were lost to
follow-up. Active members who retired during the study period were assumed to
be alive on December 31, 1979, unless mortality information was provided to
MSKCC. Seventy-two percent of the white male cohort were employed in refining
occupations. Forty-four percent of the refinery workers and 30% of the petro-
chemical workers were employed before 1960. Approximately 47% of the refinery
workers and 58% of the petrochemical workers were under the age of 40.
The SMRs for all deaths and standardized incidence ratios (SIRs) for can-
cer occurrences were calculated, and observed deaths and incidences of cancers
were compared with the expected occurrence in the general population. Mortal-
ity rates were compared with the expected occurrence in the general population.
Mortality rates were compared with U.S. white male, age-specific rates for
1977. Cancer incidence rates were compared with U.S. age-specific rates from
the National Cancer Institute's Surveillance, Epidemiology, and End Results
(SEER) programs for 1977 (SEER, 1981). MSKCC used the 8th revision of the ICD
to code diagnostic information.
Decreased SMRs were reported for all major classifications of disease.
SMRs for all deaths and all cancer deaths were significantly (p < 0.05) less
than 100 for refinery workers (SMR = 56 for all deaths, observed = 393; SMR =
75 for cancer deaths, observed = 127), petrochemical workers (SMR = 57 for all
deaths, observed = 74; SMR = 58 for cancer deaths, observed =17), and for all
workers (SMR = 55 for all deaths, observed = 502; SMR = 72 for cancer deaths,
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observed = 156). Lung cancer in refinery workers (SMR = 74, observed = 48) and
all workers (SMR = 68, observed = 57) was significantly (p < 0.05) less than
expected.
The crude average annual mortality ratio was reported to be 4.1/1,000
based on 502 deaths and 122,607 person-years of observation. The authors sta-
ted that these crude mortality results were preliminary and may be the result
of various factors, including: (1) a relatively short period of observation
to date, with workers having been followed for only 1.6 person-years on the
average; (2) the study population being younger than the U.S. population; and
(3) an underreporting of deaths due to a time lag of 4 to 5 months between the
deaths and receipt of death certificates. SMRs, on the other hand, were based
on age-specific rates. The authors acknowledged that the influence of the
healthy worker effect may have caused the standardized rates to be lower than
those expected for the general population.
SIRs were calculated for the incidence of cancers during 1977-79. There
were 307 cancers reported and 118,566 person-years of observation. For all
cancers, the SIRs were significantly (p < 0.05) less than 100 for all workers
(SIR = 85, observed « 307) and refinery workers (SIR = 86, observed = 240).
The SIR for petrochemical workers was 86, but this was not significant. How-
ever, specific cancer sites did show significantly increased (p < 0.05) SIRs:
acute and chronic lymphocytic leukemias in refinery workers (SIR = 274, ob-
served = 7), multiple myelomas in petrochemical workers (SIR = 552, observed
= 3), and cutaneous melanomas in workers from the mid-Atlantic region (SIR =
278). A significant (p < 0.05) deficit of digestive system cancer was observed
among all workers (SIR = 77, observed = 64).
The authors suggested that these figures be viewed as preliminary and
interpreted cautiously. This study looks at mortality and cancer incidence
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between 1977 and 1979. Exposure information was not included; however, because
this study was done in cooperation with the American Petroleum Industry and
specific petroleum-related companies, such information may be available. The
effects of confounding factors such as smoking and other chemical exposures
were not addressed. Additionally, the period of observation was quite short,
only 3 years, and the number of older workers in the study was limited, which
would limit the assessment of latency effects. The degree of underreporting is
unknown, but could be quite high because reporting was voluntary.
The shortcomings of this study were also discussed in a report submitted to
the EPA by the API and prepared by Environmental Health Associates, Inc. (Wong
et al., 1985 Unpublished). The main problems listed were as follows: there was
a lack of consistency in reporting of mortality and morbidity across companies;
mortality experience of terminated employees was not included; many companies
were not timely in reporting data; and verification of completeness of census
information was lacking. Thus, the results of this study provide insufficient
data to form conclusions for an association between cancer and gasoline.
4.2.1.9. Thomas et al. (1982a)—Thomas et al. (1982a) examined the cause-
specific mortality experience of an expanded group of union members who were
employed at three refineries that were included in an earlier study (Thomas et
al., 1980). These refineries were located in the Beaumont/Port Arthur area of
Texas. The number of male deaths from the original study of these three refin-
eries was 1,161. This number was expanded to include 1,194 retiree deaths and
154 additional active union member deaths. In the earlier study, reported
deaths we're for the period between 1947 and 1977. The period of observation for
the present study was extended through 1979. Thus, 2,509 active and retired
members of OCAW were available for analysis in this 1982 study. As with the
earlier study, death certificates could not be located for 8% of the reported
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deaths. As opposed to the earlier study, no Information was given regarding
length of union membership.
PMR calculations were exactly the same as for the Thomas et al. (1980)
study. Among whites, 51.2% were retirees, while less than 30% were retirees
among the non-whites. Seventy percent of the white males and 59% of the non-
white males were age 55 or older at the time of death.
An elevation in PMR was observed for all cancers in both whites (PMR
* 119, observed = 474, p < 0.05) and non-whites (PMR = 123, observed = 79,
p < 0.05), The PMR for stomach cancer was significantly elevated (p < 0.05)
for whites (PMR = 141, observed « 36) and non-whites (PMR = 196, observed
« 12). The relative frequencies of deaths, for whites only, attributable to
cancers of the pancreas (PMR = 142, observed = 32), prostate (PMR = 146,
observed » 39), brain (PMR = 228, observed = 27), and hematopoietic and
lymphatic system (PMR = 172, observed = 68), including leukemia (PMR = 189,
observed = 31), were significantly greater than expected (p < 0.05). Although
a PMR of 151 was observed for kidney cancer for white males, it was not sta-
tistically significant. A statistically significant excess was observed for
accidents, suicides, and homicides (PMR = 142, observed - 66, p < 0.05) for
blacks only.
There were differences in the mortality patterns for white males among
active and retired union members. Significant relative excesses (p < 0.05) of
stomach (PMR = 166, observed =21), pancreatic (PMR = 179, observed = 18), and
brain cancer (PMR = 229, observed = 25) deaths were seen among active members.
Among retirees, however, the PMRs were significantly elevated for prostate
cancer (PMR = 142, observed = 31), Hodgkin's disease (PMR = 365,, observed =
5), multiple myeloma (PMR = 295, observed =7), and leukemia (PMR - 232, ob-
served = 19).
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Analyses by Individual refinery revealed the following significant'(p <
0.05} PMR elevations. In Refinery A, the total (active and retired) population
showed increases in all cancers (PMR = 113, observed = 211), cancer of the
prostate (PMR = 162, observed = 20), cancer of the brain (PMR = 213, observed
* -16), and non-Hodgkin's lymphoma (PMR = 200, observed = 12). There were
significant (p < 0,05) elevations in cancer of the brain (PMR = 236, observed
= 12) and stomach cancer (PMR = 192, observed = 11) and in non-Hodgkin's lym-
phoma (PMR = 233, observed = 7) for active workers and retired workers.
In Refinery B, the cohort was analyzed by race. There were significant
(p < 0.05) PMR elevations in whites for all cancers (PMR - 122, observed =
165), cancer of the skin (PMR = 302, observed - 7), and leukemia (PMR = 252,
observed = 14), For leukemias, whites in both active and retired status
showed significant (p < 0.05) increases in leukemia (PMR = 259, observed = 7,
and PMR = 246, observed = 7, respectively). In non-whites, the significant
(p < 0.05) excesses were for all cancers (PMR = 165, observed = 43), cancer
of the stomach (PMR = 254, observed = 7), and cancer of the lung (PMR = 207,
observed = 15). Analysis by active and retiree status was not done for this
subcohort.
Refinery C showed significant (p < 0.05) increases for all cancers (PMR =
125, observed = 98), cancer of the prostate (PMR = 189, observed = 10), cancer
of the brain (PMR = 235, observed = 7), and leukemia (PMR = 260, observed = 8).
The lung cancer PMR was significant (p < 0.05) in the active members (PMR =
174, observed = 22), while the leukemia PMR was significant (p < 0.05) in
retirees (PMR = 418, observed = 6).
The limitations of this study are similar to those already noted in the
earlier study (Thomas et al., 1980). There are serious concerns regarding the
loss of individual cases due to the unavailability of death certificates^ the
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lack of exposure data, and the inherent validity problems of PMRs.
4.2.1.10. Reeve et al. (1982)—The authors reported on a proportionate mor-
tality study of members of an OCAW local in Texas City, Texas. Previous inves-
tigations had linked brain cancer with union employment in Texas (Thomas et
al., 1980), at three oil refineries in the Beaumont/Port Arthur, Texas, area
(Thomas et al., 1982a), and at a petrochemical plant in Texas City (Alexander
et al., 1982; OSHA/NIOSH, 1980). This investigation (Reeve et al., 1982) was
initiated to determine unusual patterns of cancer mortality at other refineries
and petrochemical plants in Texas City.
Males who had been union members of OCAW Local 4-449 and died during the
period 1947-79 comprised the study population. Active members at the time of
death were identified from notifications sent by the union local to OCAW
Headquarters for the purpose of maintaining an accurate count of union members;
this file had been maintained since 1947. Retired and former members were
identified from two "less well-structured record systems maintained by the
local." One system, kept since 1942, maintained a file of all deaths among
members. Names were added to the file on the basis of "word of mouth" or from
j
newspaper obituaries. The second system, kept since 1959, was a ledger of de-
ceased members whose survivors had been sent a Bible by the local.
The final study population consisted of 264 white males. Excluded because
of Insufficient numbers were black males (N = 30) and 31 deaths (11%) that
could not be documented with death certificates.
Death certificates were obtained from the Texas Bureau of Vital Statistics
and coded by a trained nosologist to the 8th revision of the ICD. Expected
numbers of deaths were obtained by applying age-, time-, and cause-specific
relative frequencies of deaths among the total U.S. white male population
(Monson, 1974). PMRs were calculated if five or more deaths were observed or
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expected. Significance testing (a = 0.05) was done using a summary ch1-
square with one degree of freedom.
Sixty-one percent of the study population had worked at Refinery A, 23% at
Refinery B, 6% at a tin smelter, 5% at a chemical plant, and the remaining 5%
at miscellaneous locations. Thirty-seven percent of the deaths occurred in the
age interval 50-59, and 20% of the deaths occurred during each of four 5-year
time periods from 1960 to 1979. The authors only reported company-specific PMR
results for the refinery workers. The authors provide no reason as to why the
non-refinery workers were excluded from the PMR analyses; however, this was
most probably due to the small numbers of non-refinery workers (40).
There were 37 cancer deaths observed among Refinery A workers (PMR = 118,
p > 0.05). Skin cancer was the only cause of death to have a significantly
elevated PMR (PMR = 788, observed =* 5, p < 0.05). Although PMRs were not,
reported, observed deaths were at least twice those expected for cancers of
the brain (observed =3, expected = 1.23) and kidney (observed = 2, expected =
0.84). The observed deaths for liver cancer were more than four times those
expected (observed = 3, expected = 0.64). An additional liver cancer death was
observed, but it could not be determined if it was primary or secondary and
was thus excluded from the PMR analysis. The only other elevated PMR was for
non-motor vehicle accidents (PMR = 163, p > 0.05).
The number of expected deaths due to melanoma, using Galveston County,
Texas, as the standard, was also determined for Refinery A workers. The re-
sulting estimate was 0.54 compared to 4 observed melanoma deaths.
Among Refinery B workers, 13 cancer deaths were observed (PMR = 108, p >
0.05). The PMR was elevated, though not significantly, for lung cancer (PMR -
156). The only other elevated PMR was for circulatory diseases (PMR = 121).
The PMR for hematopoietic and lymphatic tissue cancers was not reported, but
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the observed numbers of deaths were three times those expected (observed = 4,
expected = 1.22).
This study has several limitations. The study population may not be
representative of all union deaths in Texas City, Texas, because of the incom-
pleteness of the union's recordkeeping systems and losses due to the unavail-
ibility of death certificates. There are inherent validity problems in a PMR
analysis. There was no information on gasoline exposure, job titles, length of
employment, analysis of latency, or control of confounding factors. Thus, this
study provides insufficient data to form an association between gasoline and
cancer.
4.2.1.11. Hanis et al. (1982)—In a retrospective cohort study of the Exxon
refinery and chemical plant at Baton Rouge, Louisiana, the investigators in-
cluded all regular refinery and chemical plant employees who had worked at that
site for at least 1 month during January 1, 1970, through December 31, 1977.
Also included in the cohort were the retirees who were alive as of January 1,
1970.
Of the total population of 8,666, 6,632 were known to be alive, 1,199 were
known to be dead, and 835 (9.6%) were lost to follow-up at the end of the study
period. Data were obtained from the company personnel files that included
name, sex, race, date of birth, date of employment, social security number,
date of termination, work history summaries, status at last observation, date
of death, underlying cause of death, and, when available, a history of smoking
and alcohol consumption. Job categories were derived from the work histories.
Death certificates were available for 99% of the decedents. The underlying
cause of death was coded by a trained nosologist according to the 8th revision
of the ICD.
The computer program developed by Monson (1974) was used to calculate age,
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sex, race, and calendar year adjusted SMRs, using U.S. death rates as the
standard. Ninety-five percent confidence intervals were calculated assuming
a Poisson distribution. Hence, if the confidence interval did not include
100, the SMR was statistically significant. Reported by the authors but not
reviewed here are nonsignificant cancer excesses based on fewer than three
observed deaths.
A total population of 8,666 contributed to 52,791.3 person-years of obser-
vation. In the case of lost-to-follow-up individuals, person-years were calcu-
lated until the last known status. Ninety-five percent of the population was
male, blacks accounting for 16%, Approximately 60% of the individuals were 50
years or older, while about 50% of the individuals were employed prior to
1945. Of the study population, 72.5% belonged in the job categories of opera-
tors (32%), mechanics (60%), and laborers (8%); 25.9% belonged in all other
jobs; and 1.6% of the job categories were unknown. They were classified in
this manner because it was assumed that the first group was more likely to be
in contact with petroleum and its products.
Analyses were carried out by total cohort and various subcohorts. For the
total cohort, SMR deficits were observed for all causes of death (SMR = 92,
observed - 1,199, p < 0.05) as well as for malignant neoplasms (SMR = 92, ob-
served = 249, p > 0.05). There were more SMR deficits than increases. None of
the increases observed was statistically significant. Cause-specific cancer
mortality of this group showed elevated SMRs for cancers of the pancreas (SMR
= 152) and kidney (SMR = 155). None of these elevations was statistically
significant. There were some other SMR increases, but they were less than 120
and hence are not mentioned here. The only statistically significant SMR was
observed for cancer of the buccal cavity/pharynx (SMR = 26, observed = 2),
being a deficit. . .
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A subcohort of operators, mechanics, and laborers, consisting of 6,281
employees contributing to 38,960.3 person-years of observation, showed quite a
few cause-specific SMR increases, although none was statistically significant.
The SMR elevations of 120 or more were for cancers of the pancreas (SMR = 154),
testis/other genitalia (SMR = 286), kidney (SMR = 205), other secondary and
unspecified sites (SMR = 139), lymphoreticular sarcoma (SMR - 125), and other
lymphatic tissue (SMR = 125).
A subcohort of all other employees, consisting of 2,243 individuals con-
tributing to 13,230.3 person-years of observation, showed an SMR deficit for
all malignant neoplasms (SMR = 70, observed = 40, p < 0.05). This subcohort
showed SMR deficits for virtually every cause-specific cancer examined except
for cancers of the pancreas (SMR = 156) and bone, connective tissue, skin, and
breast (SMR = 150), with none of the elevations being statistically signifi-
cant.
Analysis of the subcohort who were alive prior to 1956, i.e., who had
worked for 15 or more years in the company (5,297 individuals, 37,425 person-
years of observation), revealed SMR deficits for all causes of death (SMR = 93,
observed - 1180, p < 0.05) and malignant neoplasms (SMR = 93, observed - 247,
p > 0.05). Statistically nonsignificant cause-specific cancer SMR elevations
of 120 or more were observed for cancers of the pancreas (SMR = 153), and kid-
ney (SMR = 155), and for lymphoreticular sarcoma (SMR = 122).
When job categories for this subcohort were considered, operators, mech-
anics, and laborers showed higher mortality than expected for cancers of the
pancreas (SMR = 154), kidney (SMR = 205), and other secondary and unspecified
sites (SMR * 141), all lymphopoietic tissue cancers (SMR = 124), and lymphore-
ticular sarcoma (SMR = 129). All of these elevations were statistically non-
significant. All other job categories showed increases for cancers of the pan-
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creas (SMR = 161) and bone, connective tissue, skin, and breast (SMR = 176).
The p value for all of these was greater than 0.05.
A special analysis of 24 pancreatic cancers did not reveal any clues as to
job category or length of employment. Importantly, alcohol consumption history
for this group was not available.
This cohort study has been fairly well analyzed. Although job categories
were considered for analysis, all potentially exposed people were considered
together. No specific gasoline exposure histories were present, and the follow-
up period was short. Analyses by latency and length of employment may have
been helpful. The study area included a chemical plant, but confounding by
other occupational exposures was not considered. No tracing procedure details
or source of death certifications were mentioned. Pancreatic cancer was the
only cancer that came very close to being a statistically significant excess
mortality than expected, but this excess was observed in the total cohort as
well as in every subcohort that was considered, leading to the conclusion that
this excess cannot be explained entirely by exposure to gasoline. Due to the
above-mentioned reasons, this study is considered inadequate to use as a basis
for drawing any conclusions,
4.2.1.12. Rushton and Alderson (1983)—On behalf of the Institute of Petroleum
in England, Rushton and Alderson conducted a retrospective cohort study of all
males who had worked for at least 1 continuous year between January 1, 1950,
and December 31, 1975, at oil distribution centers in Great Britain. Data
were provided by three companies (A, B, and C). Data collection and tracing
procedures were exactly the same as those described in these authors' earlier
(1981a) study.
The cause of death, the underlying cause of death, and up to three contri-
buting causes of death were coded using the appropriate revision of the ICD.
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SMRs were calculated by using the rates of the male population of England and
Wales for the 5-year age and calendar period. Significance testing was done
by use of the Poisson distribution.
More than 99% of the population was successfully traced. The cohort con-
sisted of 23,306 males contributing 397,569 person-years of observation, with
a mean follow-up of 17.1 years for each individual. Of 3,926 found to be
deceased, death certificates were obtained for all but 23 (0.5%) of the dece-
dents. A total of 11 job categories were considered for this study.
The SMR for all causes of death was 85 (observed = 3,926, p = 0.0001),
showing a typical "healthy worker" effect. The SMRs for all neoplasms (SMR =
87, observed = 1,002, p < 0.0001) and for cancers of the lung and pleura (SMR -
80, observed = 384, p < 0.0001), esophagus (SMR = 61, observed = 17, p = 0.02),
and intestines (SMR = 79, observed = 57, p = 0.04) showed significant deficits.
A deficit was also seen for cancer of the urinary bladder (SMR = 75, observed
= 32); this was of borderline significance (p = 0.05). Lowered mortality for
cancer of the lung was thought to be caused by a reduced level of smoking among
these workers, as compared to the level in the general population, because of
the nature of their work. The only significant SMR elevation was for myelofi-
brosis (SMR « 276, p = 0.04), which was based on five deaths.
Significant deficits were observed for many of the nonmalignant diseases:
tuberculosis (SMR = 22, observed = 11, p < 0.0001), cerebrovascular diseases
(SMR = 87, observed = 374, p = 0.01), chronic rheumatic heart disease (SMR =
52, observed = 31, p < 0.0001), other diseases of the heart excluding ischemic
heart disease (SMR = 64, observed = 71, p < 0.001), hypertensive disease (SMR
= 71, observed— 65, p < 0.01), influenza (SMR = 50, observed = 13, p < 0.01),
t
pneumonia (SMR = 72, observed = 133, p < 0.0001), bronchitis (SMR = 67, ob-
served = 240, p < 0.0001), chronic and other nephritis (SMR = 46, observed =
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15, p < 0.001), and suicide (SMR = 67, observed = 38, p < 0.0001). The only
elevation seen for nonmalignant diseases was for other diseases of the genito-
urinary system (SMR = 130, p = 0.25).
Although SMR deficits for all neoplasms and lung cancer were found in
workers for companies B and C in several job categories, they tended to de-
crease with a later date of entry into the cohort for all neoplasms. In com-
pany B, there was an excess for all neoplasms for males joining during or after
1960 (SMR = 131, observed = 43, p =0.05), which was partially accounted for by
an excess in this group for lung cancer (SMR = 163, observed = 19, p < 0.05).
An excess in lung cancer was also observed in the same company for workers who
had less than 5 years of service (SMR = 140, observed = 34, p < 0.05).
Some other statistically.significant increases were observed in some sub-
cohorts, but they were based on very few deaths. These excesses included other
neoplasms of the lymphoid tissue in workers from company C (SMR = 4.39, observed
= 5, p = 0.01) and in operators overall (SMR = 4.05, observed = 3, p =0.04);
multiple myeloma in operators from company B (SMR = 3.51, observed = 4, p <
0.05); leukemia in individuals starting work before 1940 from company B (SMR =
1.93, observed = 15, p < 0.01); and myelofibrosis in workers from company B
(SMR - 3.81, observed = 4, p < 0.05). An excess was observed from chronic lym-
phatic leukemia in company B employees when histological types were examined
(SMR = 2.33, observed = 8, p < 0.05). These SMRs were not reported by the
authors but were calculated from the authors' data as part of this review.
This is a well-conducted study as far as identification and follow-up of
the cohort are concerned. Tracing is virtually complete, and very few studies
of this size are able to achieve such a tracing success.
Although there is an indication that analyses by length of employment,
latency, and job description were carried out, no details for these variables
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were presented in this published paper; however, some of this information was
presented in the authors' unpublished version of this paper (Rushton and Alder-
son, 1982 Unpublished). The information provided is very selective and sparse.
Much of the report is devoted to a detailed analysis of various subcohorts for
ischemic heart disease, since no deficit for this cause was observed in this
study. The details of the ischemic heart disease analysis are not discussed
here, since this review pertains to cancer risk. Again, no information is
available for gasoline vapor exposure at the distribution centers or at the 11
job categories considered. In summary, the study is considered inadequate for
drawing any conclusions with respect to cancer risk.
4.2.1.13. Morgan and Hong (1983 Unpublished)—On behalf of the Standard Oil
Company of California, Environmental Health Associates, Inc. (EHA) conducted a
retrospective cohort mortality study of current and former Chevron USA employ-
ees at the Richmond and El Segundo refineries in California. Included in the
cohort of 14,179 were all individuals who had worked for at least 1 day between
January 1, 1950, and December 31, 1980, and who had completed at least 1 year
of employment at either refinery by December 31, 1980. This represented
266,470.7 person-years of follow-up.
Using company employment records, data were collected and coded on worker's
name, social security number, date of birth, sex, race (if known), date of hire,
date of separation, employment status (active, retired, separated, etc.), vital
status, vital status source, and date of death.
Names and social security numbers of cohort members identified through
employment records were matched to yearly computerized payroll tapes to verify
cohort completeness. Year-end tapes for the years 1965-66, 1970-71, and 1977-
78 were randomly selected for use. This method identified 279 (3.8%) individ-
uals not included in the original cohort. Of these, 35 records from the Rich-
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mond refinery and 96 from El Segundo were not located.
Vital status was ascertained as of December 319 1980, using records from
the company, SSA, the University of California at San Francisco's computerized
database of individuals who died in the State of California (CAMLIS), and the
California State Department of Motor Vehicles. Tracing was successful for 95%
of the cohort.
Death certificates were obtained from company records or the appropriate
states' vital statistics departments for 97.82% of those 2,292 individuals
identified as deceased. EHA's nosologist recoded all death certificates to
the 8th revision of the ICO by underlying cause of death and up to four contri-
buting causes.
Work history data, by job title, job location, and dates, were only coded
for the first and last jobs. A total of 3,324 jobs and 1,699 locations were
identified. These were classified into subgroups based on the type of work.
Seven subgroups were created for job codes: administrative/management, cleric-
al/office support, laboratory, operating, maintenance, custodial/piant protec-
tion/other, and supervisory/foreman (unknown department). Six subgroupings
were created for location codes: administration, laboratory, operating, main-
tenance, package/utilities/warehouse, and marketing/transportation.
The risk of death among the cohort members was assessed by utilizing the
SMR. The expected number of deaths was calculated by using the U.S. national
age-, cause-, race-, and sex-specific mortality rates for each 5-year time
period from 1950 to 1980 (Marsh and Preininger, 1980). Both 95% and 99% con-
fidence intervals were calculated. Those lost to follow-up were counted up
to the last date of contact (i.e., termination date or last driver's license
renewal date) and thereafter eliminated from analysis. Race was not known for
20% of the cohort. These individuals (2,772) were assumed to be white for pur-
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poses of analysis. Reported by the authors but not reviewed here are nonsig-
nificant cancer excesses based on fewer than three observed deaths.
Approximately 25% (3,465) of the cohort were active employees on the last
day of the study; 22% (3,144) retired during the study; and 42% (5,979) termi-
nated employment with Chevron. Approximately 31% were employed for 20 or more
years.
Among the total cohort, the SMR for all causes of death was significantly
low at 72 (observed = 2,292, p < 0.01) in comparison to U.S. mortality. Mortal-
ity for all cancers was also significantly low (SMR = 76, observed = 462, p <
0.01). Cancer deficits were noted for cancers of the buccal cavity and pharynx
(SMR ~ 47, observed = 9, p < 0.05), digestive system (SMR = 72, observed = 125,
p < 0.01), pancreas (SMR = 59, observed = 20, p < 0.05), large intestine (SMR =
71, observed = 40, p < 0.05), respiratory system (SMR = 69, observed = 135, p <
0.01), and lung (SMR = 67, observed = 124, p < 0.01).
Slight elevations (p < 0.05) in cancer risks were observed for cancers of
the brain/CNS (SMR = 126) and lymphatic and hematopoietic tissue (SMR = 105).
This latter group was limited to diagnoses of lympho- and reticulosarcomas
(SMR = 127) and cancer of other lymphatic tissues (ICD 202, 203, and 208) (SMR
= 142). The SMR for leukemia and aleukemia was 88, but not significantly lower
than the U.S. experience.
A large number of nonmalignant causes were observed to have statistically
significant mortality deficits; p < 0.01 unless noted. These included infec-
tive and parasitic diseases (SMR = 38, observed = 14), diseases of the nervous
system (SMR = 48, observed = 12) and circulatory system (SMR = 74, observed =
1,228), arteriosclerotic heart disease (SMR = 79, observed = 924), vascular
lesions of the CNS (SMR = 67, observed = 158), chronic rheumatic heart disease
(SMR s 61, observed = 19, p < 0.05), diabetes mellitus (SMR = 37, observed =
4-86
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17), diseases of the respiratory system (SMR =56, observed = 105), digestive
system (SMR = 65, observed = 97) and genitourinary system (SMR = 50, observed
=22), senility and ill-defined conditions (SMR = 27, observed =10), and acci-
dents (SMR = 71, observed - 146). The cause-specific SMR for suicide was sig-
nificantly elevated (SMR = 128, observed = 88, p < 0,05) over the expected.
The SMRs for all causes of death and all cancers were significantly lower
(p < 0.01) than expected at the Richmond (SMR = 74, observed = 1,507 and SMR
= 78, observed = 302, respectively) and El Segundo (SMR = 69, observed = 785
and SMR = 72, observed = 160, respectively) refineries. A slightly elevated
rate of mortality for brain/CNS cancer (SMR = 111, p > 0.05) was observed among
El Segundo workers. SMRs for all other cancer sites were less than 100 at El
Segundo, and cancers of the digestive system (SMR = 64, observed = 40, p <
0.01), stomach (SMR * 41, observed = 5, p < 0.05), respiratory system (SMR =
74, observed = 53, p < 0.05), and lung (SMR = 74, observed = 50, p < 0.05)
were significantly lower than expected.
Among Richmond refinery employees, cancer mortality rates were elevated
(p > 0.05) for cancer of the brain/CNS (SMR = 134), for lympho- and reticulo-
sarcomas (SMR = 151), and for cancers of other lymphatic tissues (SMR = 167)
and the breast (SMR = 127). The SMR for cancer of the liver was significantly
lower than expected (SMR = 25, observed = 2, p < 0.05).
White male employees (I.e., white males combined with all males for whom
race was unknown) exhibited patterns of mortality similar to that of the entire
cohort. The pattern of mortality among white females was very different from
that of white males. The SMR for all causes was only slightly lower than the
U.S. population (SMR = 93, p > 0.05), and the SMR for all cancers was slightly
elevated at 119 (p > 0.05). The only form of cancer for which a deficit was
observed was breast cancer (SMR = 68, p > 0.05). SMRs were elevated for all
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remaining cancer sites for which a death was observed. Thus, excesses (p >
0.05) were found for cancers of the digestive system (SMR = 162), large intes-
tine (SMR * 297), and lung (SMR = 242). Excesses were also observed for can-
cers of the esophagus (SMR = 994), skin (SMR = 535), kidney (SMR = 526), and
brain/CNS (SMR = 287), but these were based on only one observation.
Among those known to be non-white males, 33 total deaths were observed
(SMR = 49, p < 0.01); only 4 of these were cancer deaths (SMR = 41, p > 0.05).
No deaths occurred among non-white females during the study period.
Limiting analyses to cohort members who were classified by location into
the laboratory subcategory (N = 844) revealed nonsignificant cancer excess for
cancers of the rectum (SMR - 356), prostate (SMR = 133), and other lymphatic
tissues (SMR s 357). A significant deficit was observed for all causes of
death (SMR = 74, observed = 87, p < 0.01) and lung cancer (SMR = 27, observed
» 3, p < 0.01).
Limiting analyses to those employees who worked in maintenance locations
(N * 7,838) revealed significant cancer deficits for all cancers (SMR = 75,
observed « 266, p < 0.01) and cancers of the buccal cavity and pharynx (SMR
= 36, observed = 4, p < 0.05), large intestine (SMR = 52, observed = 17, p <
0.01), and lung (SMR = 66, observed = 72, p < 0.01). Statistically nonsignif-
icant excesses were observed for cancers of the larynx (SMR = 132), brain/CNS
(SMR = 140), and lympho- and reticulosarcomas (SMR = 129). Limiting analyses
to maintenance workers at the Richmond refinery revealed excesses (p > 0.05)
for cancers of the rectum (SMR = 137), skin (SMR = 128), testis (SMR = 144),
other lymphatic tissue cancers (SMR = 177), and a slight excess for kidney
cancer (SMR » 112).
Analyses of cohort members in operating locations (N = 5,510) revealed
excesses (p > 0.05) for cancers of the larynx (SMR = 136) and brain/CNS (SMR
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= 128), and for lympho- and reticulosarcomas (SMR = 165). Among operating
workers at the Richmond refinery, risks were also elevated for Hodgkln's dis-
ease (SMR = 179) and other lymphatic tissue cancers (SMR = 191). An excess
in leukemia and aleukemia was confined to cohort members at the El Segundo
refinery only (SMR = 197).
Analyses by the seven job classifications and the remaining three loca-
tion codes were not presented. Analyses by latency since hire (less than 10
years, 10 to 19 years, 20+ years) were presented. Among those with less than
10 years, only cancers of the kidney (SMR = 244) and other lymphatic tissues
(SMR - 135) were elevated, although these were based on only two and one obser-
vations, respectively (p > 0.05). Among workers with 10 to 19 years since
first hire, SMRs were elevated for cancers of the rectum (SMR = 132), kidney
(SMR = 125), and brain/CNS (SMR = 154), and for lympho- and reticulosarcomas
(SMR = 181) and other lymphatic tissue cancers (SMR = 263). None of these ele-
vations was significant (a = 0.05).
Among those with 20+ years of latency, elevations in cancer mortality were
observed for cancer of the brain (SMR = 119, observed = 13), lympho- and reticu-
losarcomas (SMR = 129, observed = 12), and other lymphatic tissue cancers (SMR
= 122, observed = 14). These were not statistically significant.
In addition to latency analysis, analysis for the total cohort by length
of employment at the refineries (less than 5 years, 5 to 14 years, and 15+
years) was conducted. Excesses were seen for several of the site-specific
cancers; however, none was statistically significant. The data suggest that
excesses in kidney (SMR = 284) and lung (SMR = 128) cancer are confined to
those employees with less than 5 years of employment, since no excesses were
observed among those with 5 to 14 years or 15+ years of employment. An excess
for skin cancer was observed only among those with 5 to 14 years of employment
4-89
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(SMR = 145), An elevated SMR for cancer of the brain/CNS was observed among
all three employment groups, with the greatest excess observed among those with
5 to 14 years of employment (less than 5 years, SMR = 105; 5 to 14 years, SMR
s 168; 154- years, SMR = 112). Excesses for mortality due to other lymphatic
tissue cancers were not confined to any single employment category (less than 5
years, SMR - 220; 5 to 14 years, SMR = 178; 15+ years, SMR = 121). Elevated
SMRs were only observed among those with 15+ years of experience for cancers of
the larynx (SMR = 121), lympho- and reticulosarcomas (SMR = 163), and leukemia
and aleukemia (SMR = 122). A significant deficit was observed for lung cancer
for those with 15+ years of employment (SMR = 52, observed = 70, p < 0.01).
The study population was also stratified by date of hire: pre-1949 versus
post-1948, the point in time when the recommended benzene standard (TWA) was
lowered to 35 ppm from a high of 100 ppm in 1947. All 22 leukemia deaths
occurred in employees hired on or before 1948; 16 of 17 lympho- and reticu-
losarcoma deaths occurred in pre-1949-hired employees (pre-1949, SMR = 150;
post-1948, SMR =37). Other lymphatic tissue cancer deaths followed a similar
pattern but to a lesser degree. Analyses by refinery suggest that the excess
was further restricted to those at the Richmond refinery. While these increases
are not statistically significant (p > 0.05), the authors noted that the study
had insufficient power (< 80%) with which to detect excess mortality from
malignancies of the lymphopoietic system. Among those hired after 1948, an
excess (p > 0.05) was observed for cancers of the esophagus (SMR = 144), skin
(SMR = 133), and kidney (SMR = 158).
This study had a long follow-up period (30 years) and a high percentage of
vital status ascertainment. The main limitation is the lack of information on
gasoline vapor exposure. Information on job titles was obtained but not pre-
sented. Analyses by location were presented for laboratory, maintenance, and
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operating locations; however, workers may have been exposed to more than one
substance at a single location. The authors offer no evidence that specific
high-risk jobs were accurately assessed by the coding of only first and last
jobs held. Race was assumed to be white for 20% of the male cohort; however,
no analyses were presented of the known white male subcohort to verify that no
race bias was introduced into these data. Thus, risk estimates may be overesti-
mated for this cohort. Finally, confounding risk factors were not taken into
consideration. Thus, this study is considered inadequate to draw conclusions
on the association between gasoline vapors and cancer.
4.2.1.14. Morgan and .Wong (1984 Unpublished)—This retrospective cohort study
was conducted on workers employed by the Mobil Oil Company in its Beaumont,
Texas, refinery. The cohort consisted of all individuals employed at this
refinery for at least 1 year between January 1, 1945, and January 1, 1979.
Data on the cohort were actually obtained by Stanford Research International
(SRI), which was associated with Environmental Health Associates (EHA).
Follow-up to ascertain the vital status of the eligible cohort was done through
personnel records, the SSA, Mobil corporate data, and review by refinery staff.
For the deceased members, death certificates were obtained from the refinery,
Mobil corporate offices, and various states' vital statistics departments.
Cause of death was coded by SRI according to the 8th revision of the ICD. When
death certificates were not available and the date of death was known, it was
recorded. SRI prepared the computer files for the data and edited them for com-
pleteness and consistency. SRI forwarded the edited copy of the tape to EHA.
EHA validated the data for completeness of the cohort by using union seniority
rosters, and corrected the discrepancies due to coding errors or missing data
prior to the analyses.
A total of 6,139 individuals, contributing 123,354.9 person-years of ob-
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servation, were eligible for the study; of these, 5,696 (92.78%) were males and
443 (7.22%) were females. Information on race was not available for 6% of the
cohort; for analysis purposes, these cases were assumed to be white. Vital
status as of January 1, 1979, was as follows: 4,371 (71.2%) were alive; 1,582
(25.77%) were deceased; death certificates were obtained for 98.4%; and 186
(3.03%) were lost to follow-up. Person-years were computed from January 1,
1946, or from the date of employment, whichever was later. For the lost-to-
follow-up employees, the person-years were calculated until the last date vital
status was known, and thereafter they were excluded from the analysis (with-
drawn alive).
The SMRs were computed by applying the U.S. national race-, sex-, age-,
and cause-specific mortality rates, for 5-year periods from 1945 to 1980, to
the appropriate person-years. A total of 31.63% of the cohort were hired
between 1940 and 1949, providing a potential latent period of 30 years, while
20% were hired in 1970, giving a very short period for follow-up. Analyses
~v
were carried out for the total cohort and various subcohorts by race, sex,
length of employment, and latency period.
For the total cohort, SMRs -for all causes of death and all cancers were
81»3 (observed = 1,582) and 96 (observed = 346), .respectively, the former being
significant (p < 0.01). There were more SMR deficits observed than excesses.
Some of the deficits were statistically significant, including the ones for
diseases of the circulatory system (SMR - 86, observed - 896); nonmalignant
respiratory diseases (SMR = 51, observed = 59); diseases of the digestive sys-
tem (SMR = 59, observed = 50) and genitourinary system (SMR = 52, observed =
21); accidents, poisonings, and violence (SMR = 58, observed =91); and cancers
of the buccal cavity and pharynx (SMR = 27, observed = 3), digestive system
(SMR = 76, observed = 86), and rectum (SMR = 24, observed = 3). Excess mortal-
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ity (p > 0.05} was observed for the following causes: cancer of the skin (SMR
= 139), cancer of the breast (SMR = 147, based on three cases), lympho- and
V
retlculosarcomas (SMR = 147), and other lymphatic tissue cancers (SMR = 158).
Statistically significant findings were noted for lymphatic and hematopoletic
cancer (SMR = 147, observed =47), and leukemia and aleukemia (SMR - 173,
observed =23).
The subcohort of 4,733 white males (including 358 for whom race was not
known but who were classified as white), contributing a total of 98,070.4 per-
son-years, had SMR deficits for all causes of death (SMR = 84, observed =
1,233, p < 0.01) and all cancers (SMR = 92, observed = 256). The only signifi-
cant excess observed in this group was for lymphatic and hematopoietic cancer
(SMR * 148, observed = 39, p < 0.05), an excess that came primarily from the
leukemia and aleukemia category (SMR = 179, observed « 20, p < 0.05).
This group also showed an insignificant excess incidence for the same
causes of cancer mortality as those of the total cohort, except for breast can-
cer. Significant deficits observed for cancer were similar to those observed
for the total cohort, except that liver cancer was also observed at signifi-
cant levels (SMR = 16, observed » 1). The SMR deficits for causes of mortality
other than cancer were also similar to those of the total cohort.
The subcohort of 418 white females, contributing 6,882.4 person-years,
also had lower mortality than expected for all causes of death (SMR = 59,
observed » 17, p < 0.05) and all cancers (SMR = 97, observed = 8, p > 0.05).
A few increased SMRs were observed, but they were neither significant nor
represented by more than one case, except for breast cancer (SMR - 151), which
was based on only three cases (p > 0.05).
The male non-white subcohort consisted of 963 individuals contributing
18,205.2 person-years of employment. The SMR for all causes of death was lower
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than expected (SMR = 74, observed = 331, p < 0.01) but was increased slightly
for all cancer deaths (SMR = 110, observed = 82, p > 0.05). Nonsignificant
elevations of SMRs were found for some types of cancer, one of them being
cancer of the respiratory system (SMR - 128). The increased SMR for respira-
tory cancer was caused solely by the increased incidence of death from lung
cancer (SMR = 138), and was based on 25 cases. Elevated SMRs were also seen
for prostate cancer (SMR = 128), stomach cancer (SMR = 133), leukemia and
aleukemia (SMR ~ 163), other lymphatic tissue cancer (SMR * 181), and a slight
increase for pancreatic cancer (SMR = 119).
The subcohort of all male employees had SMR deficits for all causes of
death (SMR * 82, observed - 1,564, p < 0.01) and all cancers (SMR = 96, observed
= 338). The findings for this subcohort were identical to those for the total
cohort, with significantly increased SMRs for the same two causes of cancer
mortality, lymphatic and hematopoietic cancer (SMR = 148, observed a 46, p <
0.05), and leukemia and aleukemia (SMR = 177, observed = 23, p < 0.05). Results
for this group were unchanged when the 358 individuals whose race was unknown
were excluded from the group.
When the data for white males were examined by length of employment and
latency period, the SMRs for all causes of death and for all cancers showed
positive trends, by increasing length of employment and increasing latency
period, SMRs for all causes of death consistently showed a statistically sig4-
n1fleant deficit in all the groups, except in the group that had a latency
period of more than 40 years. A definite positive trend was observed for mor-
tality from lung cancer with increasing latency, although the SMRs for each
group were lower than 100. Similar trends were not observed for the same cause
by length of employment. Positive trends with increasing latency were also
observed for brain cancer and cancer of the central nervous system, and for
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lymphatic and hematopoietic cancer. A similar trend was observed for the
latter cause but not the former when length of employment was considered.
Surprisingly, no positive trend was observed for mortality from leukemia and
aleukemia, either by length of employment or by latency. SMRs were statis-
tically significantly increased for lymphatic and hematopoietlc cancer in the
group with a latency period greater than 40 years (SMR = 190, observed = 16),
and for leukemia and aleukemia in the group with a latency period of 20 to 39
years (SMR = 215, observed = 11) and the group employed for more than 30 years
(SMR = 235, observed =11). A statistically significant excess of skin cancer
was observed among those with less than 20 years' latency (SMR = 375, observed
- 4,).
Among non-whites, positive trends were observed for all causes of death
when the data were analyzed by length of employment as well as by latency
period. The SMRs for all causes of death showed significant deficits in both
the less than 20 and the 20 to 39 years' latency groups (SMR = 60, observed =
40, and SMR = 57, observed = 127, respectively). The SMR for all causes of
death in the 40+ year latency group was only slightly elevated (SMR = 106, p >
0.05). Although a positive trend for all cancer types was observed by latency,
no such trend was evident by length of employment. The SMR for all cancers in
the group with a latency period of 40+ years was 154 (observed = 45, p < 0.05).
Increased SMRs for this group were also observed for cancer of the respiratory
system (SMR » 237, p < 0.01), which included lung cancer (SMR » 255, p < 0.01);
both of these increases were based on 17 cases each. Analysis by length of em-
ployment showed significant excesses in mortality from cancer of the digestive
system (SMR = 439, p < 0.05) and cancer of the stomach (SMR = 756, p < 0.05),
both in the group employed for less than 10 years. These SMRs were based on a
very few cases (five and three cases, respectively). Curiously, the incidence
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of stomach cancer showed a negative trend both by latency-and length of employ-
ment.
A special analysis for lymphatic and hematopoletlc cancer for all males
revealed findings similar to those for white males and showed a positive .trend
by both latency and length of employment, although the gradient was modest.: No
such trends were observed for leukemia or aleukemia either by latency or by ,
length of employment. When this cohort was subdivided into groups of persons
hired prior to 1957 (when the recommended benzene 8-hour TWA exposure limit
value was 35 ppm) and those hired after 1957 (when the recommended benzene 8-
hour TWA exposure limit value was lowered to 25 ppm), there were 45 deaths in
the former group (SMR » 148, p < 0.05) and one death in the latter group (SMR
« 121, p > 0.05). Leukemia SMRs for these groups were 174 (p < 0,01) and 300
(p > 0.05), respectively. , ...
This study has a long follow-up period of 35 years and a high percentage,
of vital status ascertainment for a cohort having such a long follow-up. The
analyses are fairly complete and well done. The main limitation of this study
with regard to the evaluation of the carcinogenicity of gasoline vapors is the
lack of information on exposure. No surrogate information, such as job titles,
was reported. Also, no details of the follow-up procedures are available. The
SSA was the only external source of information, ,so it is likely that a few
deaths were missed. Finally, confounding by risk factors could not be evalu-
ted for this study.
4.2.1.15. Thomas et al, .(1984)—This is a nested case-control study of de-
ceased OCAW members who had been employed in three Texas oil refineries. The
original description of decedents from active and retired union members can be
found in the authors' earlier proportionate mortality study (Thomas et al.,
1982a) where significant (p < 0.05) excesses of mortality from malignant brain
4-96
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tumors, stomach cancer, and leukemia were reported. Also reported earlier were
the authors' preliminary analyses of the brain tumor case-control data (Thomas
et a1.t 1982b). However, since the number of cases has since expanded, from 25
observed deaths among active employees to 37 observed deaths among active and
retired employees, only the later study (Thomas et al., 1984) is reported here.
One brain tumor case, four stomach cancer cases, and four leukemia cases
were subsequently added to the original data (Thomas et al., 1982a) for this
study. Of the 37 total brain tumor cases, six were excluded from analysis be-
cause the diagnoses could not be confirmed with hospital records. (Diagnoses
of brain tumors were confirmed because the brain is a common site of metasta-
sis.) One leukemia case was excluded because additional Information Indicated
that an incorrect diagnosis was obtained originally.
The 31 brain tumor cases, 52 stomach cancer cases, and 34 leukemia cases
were matched to three deceased controls selected from the records of active and
retired union members. Cause of death was any other than those under study.
Controls were matched to the cases for race, sex, and refinery, and were
matched as closely as possible for age at death, date of death, and date of
first union membership. Work history records could not be located for 16
controls, so substitute controls were selected; records for 8 of these substi-
tutes were not located and were eliminated from the study. Thus, there were 93
controls matched to the brain tumor cases, 154 controls matched to the stomach
cancer cases, and 96 controls matched to the leukemia cases.
!*
Cases of multiple myeloma (N - 9), Hodgkin's disease (N = 9), non-Hodg-
kin's lymphoraa (N = 23), and cancers of the skin (N = 14), prostate (N = 51),
and pancreas (N = 41) were also obtained to develop crude estimates of unusual
employment patterns by work categories. The controls for the brain tumor cases,
stomach cancer cases, and leukemia cases served as the control population, as
4-97
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the original pool of eligible controls had been exhausted.
Eleven mutually exclusive work categories were created by categorizing
the types of unit operations. Assignment to work categories was accomplished
by reviewing job titles and department assignments. No quantitative exposure
estimates were attempted.
Five of the work categories established had unit operations in which gas-
oline was identified or was known to be a constituent product. Category 1
(crude oil) had jobs associated with the "first step" in the refining process,
including the distillation of crude oil into five basic streams, one of which
was wet gas and gasoline. Category 3 (treating) included jobs related to the
production of gasoline, kerosene, light fuel oils, and diesel oils. These
processes included blending of additives, alkylation to produce high-octane
products, polymerization to improve the quality of gasoline products, and hy-
drogen-treating to remove sulfur. Category 7 (maintenance and labor) included
all functions related to equipment servicing, maintenance, and construction,
including still and tank cleaning. Category 8 (receipt and movement) included
all processes, areas, and equipment used for the transport of bulk liquid
products, e.g., gasoline. Category 9 (laboratory) included the quality control
laboratories where refinery products such as gasoline are tested. The defini-
tions for the remaining six work categories of lube oil (category 2), coking
(category 4), grease paint (category 5), utilities (category 6)s motor trans-
portation (category 10), and other activities (category 11) indicated no expo-
sure to gasoline.
A study subject was considered exposed to a work category if he was known
to have worked at least 1 day in a category beginning 15 years or more prior
to his death. Approximately 40% of the study population met the definition
of exposure for at least one category. As many as six exposure categories per
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individual were observed, but the average number of categories was two per
study subject.
Estimates of relative risk (odds ratios) by work category for brain tumors,
stomach cancer, and leukemia were calculated by the maximum-likelihood method,
using Miettinen's procedures for matched case-control data. Odds ratios were
not calculated if the number of exposed cases was less than five, and were con-
sidered statistically significant if 90% confidence intervals did not contain
1. The authors noted, however, that statistical significance testing was used
as "a guide to the relative importance of the numerous comparisons made" and
was "not to be interpreted in the strict(est) sense." The Mantel extension
procedure was used to examine trends by length of time for those work cate-
\
gories in which the odds ratio was 1.5 or greater. Also reported were median
f
durations of employment for those who were exposed in each work category.
Matching was eventually dropped, and levels for duration of employment were
defined as (1) not exposed, (2) exposed but worked less than 5 years in the
category, and (3) exposed and worked more than 5 years in the category. Final-
ly, standardized risk ratios (SRRs) were calculated for exposure levels 2 and
3, using the lowest exposure level as the standard.
A significantly elevated odds ratio (p < 0.10) of 2.8 was observed for
brain tumor cases among receipt and movement workers; however, median duration
of employment for the cases was 22% of that of the controls. Similarly, brain
tumor cases who were pipefitters (a subcategory of maintenance and labor) (OR =
1.5), workers in the overall category of maintenance and labor (OR = 1.2), and
lube oil workers (OR = 1.6) also had elevated, although not significant, odds
ratios. Median duration of employment for the controls approximately equaled
or exceeded that of the cases. All of these work categories, except the latter
(i.e., lube oil), had potential for gasoline exposure.
4-99
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Odds ratios for stomach cancer were significantly elevated (p < 0.10) for
maintenance and labor workers (OR = 4.5), the yard labor subcategory (of main-
tenance) (OR = 2.4), and lube oil workers (OR = 1.7). Odds ratios were eleva-
ted for the maintenance subcategories of pipefitting (OR = 1.8) and miscella-
neous maintenance (OR = 1.7). Median duration of employment for cases was ,;
longer than for the controls for each of these work categories/subcategories.
Odds ratios were also elevated for the maintenance subcategories of boilermak-
ing (OR - 1.5) and construction (OR = 1.2) and the category of motor transpor-
tation (OR = 1.7); however, median duration of employment was longer for the
controls in comparison to the cases for each of these latter groups. Again,
all of these work categories, except lube oil, may have had potential for
gasoline exposure.
No significantly elevated odds ratios were observed for leukemia among the
study population. Risks were elevated for the treating category (OR = 1.6) and
the boilermaking subcategory of maintenance (OR = 1.5). The median duration
for the cases was longer than that for the controls for both of these work
category employees. Both of these work categories had potential for gasoline
exposure. Odds ratios for lube oil workers were slightly elevated (OR = 1.1),
but the median duration of employment for the controls was nine times longer
than for the cases.
A nonsignificant dose-response trend for duration of employment (measured
as no employment in a work category, less than 5 years' employment in a work
category, and 5 or more years' employment in a work category) was observed for
stomach cancer for lube oil workers (0 years, SRR = 1.0; < 5 years, SRR = 1.5;
> 5 years, SRR = 1.8) and maintenance workers (0 years, SRR = 1.0; < 5 years,
SRR == 2.4; > 5 years, SRR = 3.1), and for leukemia among workers in treating
(0 years, SRR = 1.0; < 5 years, SRR = 1.2; > 5 years, SRR = 2.0) and boiler-
4-100
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making (0 years, SRR = 1.0; < 5 years, SRR = 1.2; > 5 years, SRR = 1.8). The
stomach cancer data for which a dose-response trend was evident were further
analyzed by refinery. (Leukemia data were not analyzed because of the small
number of cases per refinery.) Risks for cases who worked with lube oil (OR
= 3.1, p < 0.10) and maintenance (OR = 3.6, p > 0.10) were more than three
times those of the controls at Refinery A. Elevated risks (p > 0.10) were
also observed at Refinery B among lube oil workers (OR = 1.5) and maintenance
workers (OR = 2.4). At Refinery C, risks were elevated for maintenance workers
(OR = 3.3). Again, each of these work categories, except lube oil, had poten-
tial for gasoline exposure.
A comparison of the multiple myeloma, Hodgkin's disease, non-Hodgkin's
lymphoma, skin, prostate, and pancreas cancer cases with the pooled controls
revealed no pattern by work category.
These results provide very weak evidence for an association between work in
the petroleum industry and stomach cancer. A dose-response trend was observed
for stomach cancer among the maintenance workers, a work category for which a
potential for gasoline exposure exists. Among all maintenance workers, the
estimate of relative risk was high (OR = 4.5) and significant (p < 0.10). The
median duration of employment for the cases was longer than for the controls.
Similar patterns were observed for lube oil workers (a work category not con-
sidered to have potential for gasoline exposure), but the estimates of risk
were not as elevated as they were for maintenance workers.
The major limitation of this study, as with most of the studies of refin-
ery workers, is the inability to determine gasoline exposure. As the authors
noted, "It is not known if the work categories, were truly indicative of expo-
sure, since the number of potential exposures in any particular category was
extensive, and because workers may not have had contact with a specific sub-
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stance in more than one category." The authors set « at 10% rather than at
the customary 5%; thus a larger porportlon of the significant findings may be
due to chance alone. Also, there was no control for confounding factors'such
as alcohol and other chemical exposures.
The cases and controls, all of whom worked at the oil refineries, may be
overmatched with respect to occupational exposures within the refinery if there
is a common exposure for this population that causes certain types of cancer.
However, this would tend to underestimate the estimate of relative risk and
thus 1s not considered a serious limitation.
4.2.1.16. Men et al. (1984b Summary)—This document, hereinafter referred to
as Wen et al. (1984b Summary), describes and summarizes the findings from seven
different studies. Six of these studies were carried out on Gulf Oil Company
refinery employees, and one was carried out on populations from counties in
which refineries are located. Data were presented primarily for kidney cancer.
1. Study of kidneycancer mortality In Jefferson and Orange Counties (Texas)
These two counties have a heavy concentration of refineries and petro-
chemical plants and hence were chosen for the study. Of 24,766 deaths in these
counties between 1965 and 1981, 99 deaths were due to kidney cancer. When com-
pared with the rate for the U.S. general population by age, race, and calendar
time, the SMR was found to be 100. There was a modest increase in kidney'can-
cer in the 1970-74 period (SMR » 138, 95% CI 99-188), but no positive trend was
found.
2. A cohort study of Gulf's Port Arthur refinery
This study was published in 1983 and is reviewed earlier in the document
as Wen et al. (1983).
3. A mortalitysurveillance study of all of Gulf's employees and annuitants
A total of 246,263 person-years were contributed to this study by 48,417
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males and 12S916 females during the 1977-81 mortality surveillance period. Of
3,046 deaths occurring during this periods 16 were attributed to kidney cancer
in males. The SMR of 92 was based on the U.S. population and was not statisti-
cally significant (95% CI 53-150). No deaths were observed among the females.
Deficits were also observed for deaths from bladder cancer (SMR = 49) and
genitourinary system diseases (SMR = 58). No other details of the analysis
were provided.
4. A cancer incidence study of Gulf ' s refineries and petrochemical plants
A cancer registry established in 1977 for Gulf's 18 refineries and
petrochemical plants monitors about 15,000 employees; among these employees,
two kidney cancer deaths (observation period unknown) were seen, which gave a
standardized incidence ratio of 70 (95% C! 8-252), I.e., indicating no increase
in kidney cancer in this population,
5. A hi s^or1ca_^mortality analysis of Gulf employees and annuitants JPMR
~
A total of 17,511 death certificates were collected during the period
1932-82 for Gulf employees and annuitants who had died either while employed or
after retirement. A PMR analysis was conducted using Monson's (1974) program.
The PMR for kidney cancer was 114 for whites (observed » 81), 139 for non-whites
(observed = 4), and 115 for all males (observed = 85). None of these was
statistically significant. PMR deficits were seen for bladder cancer among
whites (PMR = 75, observed = 82) and among non-whites (PMR = 83, observed =4).
6- Qa>e^coQt. sy ^ or tlle P°rt Arthur cohort
Twenty-two deaths from kidney cancer were identified in the retrospective
cohort study described earlier (Wen et al., 1983). For each case, three non-
cancer-deceased controls (d.c.), matched on race, sex, date of birth, and date
of death, and three mixed controls (no exclusion for cancer, dead or alive)
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(m.c.), matched with the entire cohort for race, sex, date of birth, date of
hire, and length of service, were selected. Matched analyses using Rothtnan
and Boice's (1982) program were done for gasoline, jobs ever held, longest job
held, smoking, and alcohol.
Eleven certified Industrial hyglenlsts derived estimates of exposure to
gasoline; the hyglenists Individually assessed exposure for 1,000 job titles.
Smoking and alcohol histories were obtained from medical records of either
preplacement or voluntary health examinations.
Comparison with each of the control groups and for the different lengths
of exposure to gasoline vapors showed no significant excess in relative risk
of kidney cancer for the cases (RR m.c. * 1.09, 95% CI 0.34-3.55; RR d.c. =
0.82, 951 CI 0.24-2.81). There was also no evidence of a dose-response rela-
tionship by duration of exposure. Similar results were observed for the sub-
group of cases with 20 or more years of employment. A modest increase in
relative risk was observed for these cases when compared with the m.c. group
exposed for 6 months up to 5 years (RR = 2.37, 95% CI 0.62-9,09). This result
contradicts the expectation that comparison with the d.c. group would show an
increase in relative risk, since this control group was made up of non-cancer
individuals, as opposed to the m.c. group, which did not exclude persons with
cancer.
Relative risks using m.c. were higher than those using d.c. when the
analyses were done by job titles; lube oil workers (RR m.c. = 6.00, 95% CI
0.73-49.34; RR d.c. = 3.00 95% CI 0.46-19.36), garage and transportation work-
ers (RR m.c. - 3.16, 95% CI 0.42-24.20; RR d.c. = 2.20, 95% CI 0.35-14.10), and
receipt and movement workers (RR m.c. = 2.30 95% CI 0.32-16.43; RR d.c. = 1.22,
95% CI 0.22-6.92) for the longest-held jobs. Relative risk for kidney cancer
was increased for cases working in the utility department when compared with
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the d.c. group (RR = 4.37, 95% CI 0.44-43), but not when compared with the tn.c.
group (RR = 1.00). The authors point out here that in the workers from the
garage and transportation department, the controls had worked longer in this
department than the cases.
When the risks for groups of employees from the various departments were
examined by job ever held, the grease plant workers showed an increased rela-
tive risk for cases when compared with the m.c. group (RR = 3.00, 95% CI
0.21-41,92). Again, the authors note that the controls had spent a longer
time than the cases in the grease plant.
None of the relative risks was statistically significant, and the numbers
on which they were based are very small. The authors also state that these
excesses were due to non-gasoline causes, since gasoline exposure effects were
already examined. This is a little difficult to accept in the absence of any
simultaneous multiple adjustment analysis for confounding factors, since the
risks may be additive or multiplicative.
Smoking and alcohol Intake information was available for fewer than one-
third of the cases (i.e., seven individuals) as well as for the controls;
nevertheless, an analysis by these factors was carried out, and twofold and
threefold increases in the relative risk for kidney cancer were found for
these cases, respectively. It is interesting to note that smoking and some-
times alcohol consumption have been cited as risk factors for kidney cancer.
7. Acomparison of exposure between "refineryworkers" and workersat market-
ing and gasoline stationjs'
Total hydrocarbon exposure was measured at refineries and at marketing and
gasoline terminals. Personal samples for the entire work period (7 hours or
more) or partial samples (short-term peak periods) and area samples were col-
lected. Results for the entire work period sampling indicated that marketing
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terminal workers had slightly higher exposures than refinery workers; the 95th
percentile was 30 ppm and 20 ppm, respectively, but neither of them was any-
where near the recommended TLV of 300 ppm. Service station workers also had a
very low exposure, with an average of 3.1 ppm TWA; the TWAs for refinery and
marketing terminal workers were 5 and 11 ppm, respectively. The area samples
showed a mean of 15.2 ppm for refineries and 13.4 ppm for marketing terminals.
The partial samples showed a mean of 13.7 ppm for refineries and 71.5 ppm for
marketing terminals; the 95% percentile for marketing was 340 ppm.
Conclusions of the Wen et al.(1984b Summary)Study
This conclusion section describes the kidney cancer results reported by
Wen et al.; in this paper, the authors compiled data from seven studies, six
of which involved Gulf Oil Company employees and one that concerned kidney
cancer deaths among individuals living in Texas counties containing a large
number of refineries and petrochemical plants. Each of these seven studies is
reviewed above; studies 5, 6, and 7 are discussed here, since only these three
studies of the group of studies discussed by Wen et al'. have relevance for a
review of the cancer epidemiology of gasoline-exposed workers.
Study No. 5 looked at PMRs and therefore suffers from all the Inherent
validity problems of a PMR study.
Study NO. 6 is the most important of the studies 1n the Wen et al. paper.
However, this case-control study has a number of limitations. The sample size
is extremely small. No indication is given of the population from which the
deceased and/or mixed-control individuals were selected. No information is
provided for the assumptions used to Interpret the results obtained by com-
parison with the mixed-control group. The mixed-control group contains indi-
viduals with cancer, which may have led to an underestimation of risk for these
cases if kidney cancer and the types of cancer found in the controls had the
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same risk factors. Adjustment fop confounding factors was not done. Histories
of smoking and alcohol consumption are lacking in two-thirds of the cases as
well as for the controls, and probably would not have been of use even if
available because they were obtained from preplacement and/or voluntary health
examinations. Exposure history to gasoline vapor is available by length of
exposure but not by the level of exposure.
The final Wen et al. study (Study No. 7) was supposed to address the pro-
blem of the lack of information on exposure intensity. It does not, however,
because the exposure levels measured in that study cannot readily be applied
retrospectively, since past exposures may have been considerably different.
Furthermore, the method of collection of personal as well as area samples, the
method of estimation of hydrocarbons, the duration of the collection period,
and whether or not the samples were collected for different shifts were not
explained. Also, the study did not report exposure levels by job titles. In
summary, the studies reported in the Wen et al. summary paper are considered
inadequate for qualitative risk assessment.
4.2.1.17. Kaplan (1982 Unpublished, 1985 Unpublished)—On behalf of the
American Petroleum Institute, Kaplan (1982 Unpublished, 1985 Unpublished) con-
ducted additional follow-up and analyses on API's retrospective cohort mortal-
ity study of approximately 20,000 people from 17 refineries. Previously repor-
ted by Tabershaw-Cooper Associates, Inc. (1974 Unpublished, 1975 Unpublished),
Kaplan's initial analyses (1982) added an additional 5 years of follow-up. He
subsequently (1985) added an additional 4 years of follow-up for a total of 19
years of cohort follow-up. Reported here is the latest of these analyses
(Kaplan, 1985 Unpublished).
Included in the cohort were male, non-clerical, hourly workers on their
last job (except for petrochemical workers, who were excluded wherever possible)
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who had worked continuously for at least 1 year between 1962 and 1971. Females,
petrochemical workers, clerical workers, and salaried workers were excluded.
Refinery No. 5 was excluded from the analysis because it did not have records
beyond 1 year for workers who had left or been terminated.
Vital status of the cohort was updated through December 31, 1980, through
the SSA as well as through participating refineries. Between these two sources,
the SSA information was assumed to be correct except where vital status was
known to the refinery and unknown to the SSA. Refineries also updated employ-
ment status for each individual and provided information on race where possible.
Race information was missing for approximately 7.5% of the cohort. Death cer-
tificates were obtained from various state vital statistics departments. The
author did not indicate the ICD revision used to code the death certificates.
Person-years of observation were used for the analysis. The expected mor-
tality for black males was derived using the mortality experience of non-white
males. Mortality for "other males" was compared with white male mortality.
The results from both were then, combined. SMRs were computed by using the
modified life table program adapted from Monson (1974). For analysis of brain
cancer and brain neoplasms, the NIOSH program was used (Waxweiler et al.,
1983b). For the multiple myeloma mortality analysis, U.S. population rates
were used.
Of 20,169 individuals, 178 (0.9%) were excluded from the cohort for various
reasons, reducing the cohort size to 19,991. Through December 31, 1980, 15,935
were alive, 3,349 were dead, and 707 (3.5%) were lost to follow-up. The mean
age at time of hire for this cohort was 26.2, and over 66% of the cohort was
employed for more than 20 years as of this update.
For the total cohort analysis, including 297,591.9 person-years of employ-
ment, significant (p < 0.05) SMR deficits were observed for all causes of death
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and for mortality from all cancers (SMR = 78, observed = 3,349S and SMR = 87,
observed - 793, respectively). More SMR deficits than excesses were observed
in this population. Some of the noteworthy statistically significant deficits
were for cancer of the respiratory system {SMR = 83, observed = 278, 95% CI
73-93)» lung cancer (SMR = 85, observed ~ 270, 95% CI 75-96), diseases of the
circulatory system (SMR = 79, observed = 1S727, 95% CI 75-83), and ischemic
heart disease (SMR = 80, observed = 1,267, 95% CI 76-85). SMRs above 120 were
observed for mortality from cancer of the thyroid (SMR = 122), cancer of other
lymphatic tissue (SMR = 131), and from benign neoplasms (SMR = 133). These
excesses were based on 2, 30, and 14 deaths, respectively,, None of these SMRs
was statistically significant.
The SMRs for the subcohort of whites only, for the subcohort having at
least 10 or 20 years of latency, and for the subcohort employed for at least
10 years were similar to the SMRs for the total cohort (as stated in the text,
although no tables are given). For the subcohort that had 20 or more years of
employment, the results were also similar, except for mortality from cancer of
the thyroid, which showed an SMR deficit, and an excess (p > 0.05) of mortality
from neoplasms of the lymphatic and hematopoietic tissue (SMR = 111,).
Three special analyses were carried out; two of these were for causes of
excess mortality observed in the total cohort and in virtually all of the sub-
cohorts. They are as follows:
A special analysis of mortality from cancer of other lymphatic tissue re-
vealed that of 30 deaths, 16 were attributed to multiple myeloma, with a mean
age at death of 63.5 years and an SMR of 123 (p > 0.05), Other deaths in this
group were caused by polycythemia vera (4 deaths) and other neoplasms of the
lymphoid tissue (10 deaths).
A special analysis of mortality from benign neoplasms revealed that of 14
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deaths, 7 were due to unspecified brain neoplasms, with an SMR of 127 (p >
0.05).
The third special analysis was for mortality from mesothelioma. In the
total cohort, there were nine mesothelioma deaths; six of them were caused by
pleura! mesotheliomas, while for the other three it was not clear whether
pleura! or peritonea! surfaces were involved. The job status of these cohort
members was as follows: one insulator, one maintenance supervisor, one pipe-
fitter, one utility worker, two welders, and three machinists. The average
duration of employment was 30.22 years and the SMR was 241 (p < 0.05).
This study of 19,991 individuals definitely has good statistical power,
and the follow-up to date is very good. The cohort is quite young, however.
Analyses are done by race, length of employment, and latency, though no tables
are provided. Once again, vital Information on exposure to gasoline vapor is
missing, as is an analysis by job titles. Confounding factors are not con-
sidered.
It is interesting to note the increase in mortality attributed to meso-
thelioma. This may be a real increase, because the author notes that some of "
the workers might have worked during World War II in shipyards where there may
have been asbestos exposure. The history of current and/or past potential
exposures to other occupational substances is missing. There is also a slight
chance of misclassification, as pointed out by the author, but misclassifica-
tion can lead either to overestimation or to underestimation, depending on
whether the error is one of commission or omission.
4.2.1.18. McGraw et al. (1985)—The authors conducted a retrospective mortal-
ity study of white male Shell Oil Company employees from the Wood River Refin-
ery in Southern Illinois. The refinery produces a "full line of refinery
products." A research laboratory operated on the site from 1933 to 1975. The
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cohort of 3,976 (person-years of observation not reported) consisted of all
white male employees (hourly and salaried) who had worked at the refinery for
at least 1 day during the period January 1, 1973, through December 31, 1982.
Retirees who were alive as of January 1, 1973, and whose last work location was
the refinery were also included. Vital status was ascertained as of January
1, 1983, by company pension and life insurance departments. Lost to follow-up
were all employees (8%) who terminated employment for reasons other than retire-
ment; 94% of this group was under 40 years of age, and 73% had 5 years or less
of employment. - ,
Death certificates were obtained from company pension files or state vital
statistics departments. Underlying cause of death was coded to the 8th revision
of the ICO by a trained nosologist. Person-years were accumulated from January
1, 1973 (or date of employment 1f after January 1, 1973) to date of death, date
of termination, or study end date, whichever came first. The SMRs adjusted for
age were calculated (Monson, 1974) using U.S. white male death rates as the
standard. Cell-type-specific SMRs were calculated using the Surveillance, Epi-
demiology and End Results (SEER) mortality rates for white males, all regions
combined, 1973-77 (SEER, 1981). The SMR 95% confidence intervals were also
estimated.
On the day of entry into the cohort, the mean age of the population was 49
years. Half of the cohort began employment before 1948; approximately two-thirds
were pensioners before the end of the study period.
There were 640 deaths observed. The SMR for all causes was 76 (p < 0.05)
and for all cancers was 91 (p > 0.05). A significant elevated SMR was observed
for leukemia/aleukemia (SMR = 213, observed =14, 95% CI 117-358). Significant
deficits in the SMR were observed for nonmalignant diseases of the circulatory
system (SMR = 77, observed = 361, 95% CI 69-85), respiratory tract (SMR = 44,
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observed * 28, 95% CI 29-63), and digestive system (SMR = 49, observed = 15,
95% CI 27-81). Not reported, but representing 139 observed deaths, were cancers
of the buccal cavity and pharynx, stomach, large intestine, rectum, liver, pan-
creas, larynx, lung, skin, prostate, testes, bladder, kidney, brain, and central
nervous system.
Cell type for 12 of the 14 observed leukemia deaths was specified on the
death certificate. Eight of these were acute myelogenous cell type (AMI) (SMR
3 394, 95% CI 172-788). No deaths due to lymphosarcoma or reticulosarcoma were
observed. Work histories for cohort members whose cause of death was leukemia
were reviewed using payroll records and preemployment application forms. None
of these employees were "operators in the benzene units or loaders in the
dispatching department," Five were maintenance workers, three held laboratory
jobs, and six (two draftsmen, one patrolman, and three compounders) "probably
had no benzene exposure above refinery background level."
No data on exposure to gasoline vapors were presented in this study. The
study site also included a research laboratory. All employees who terminated
employment for reasons other than retirement were lost to follow-up (approxi-
mately 318). This may lead to an underreporting of cohort mortality, particu-
larly if those employees who terminated did so for reasons of disability. No
analysis by latency was presented, although the authors stated that about half
of the cohort began employment before 1948. The follow-up period was short.
Analysis by specific cancer sites was limited to lymphatic and hematopoietic
tissues. Finally, confounding factors were not considered. Because of the
above-mentioned reasons, this study provides insufficient evidence of an asso-
ciation between gasoline and cancer.
4,2.1.19. Hanis et al. (1985a)—In the first part of this, multiple-objective
study, the authors used a retrospective cohort study designed to examine the
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mortality experience of regular employees who had worked for at least 1 month
in the plants under study during the period January 1, 1970 through December
31, 1977. The cohort population came from three Exxon refineries and chemical
plants situated In the United States. It also Included retirees who were alive
as of January 1, 1970. Employees who worked In more than two plants were
counted only once In the total population, although their duration of employ-
ment at all plants combined was counted appropriately in person-years. Data on
name, date of birth, sex, race, date of employment, date of termination, and
vital status at last observation were obtained through company, personnel, and
medical records. Data on the underlying cause of death were extracted from
death certificates. The underlying cause of death was coded by a trained
nosologist according to the 8th revision of the ICD. Where death certificates
were unavailable, death notices or company medical records were used. SMRs
were computed by using the U.S. cause-specific mortality rates by age, race,
sex, and calendar year for each 5-year age group.
The total cohort consisted of 21,698 Individuals, which included 15,437
regular and 6,261 retired employees contributing 137,702 person-years of employ-
ment. Forty-two percent of the cohort were still actively employed at the end
of the study period, 46% had retired (29% of these died during the study period),
10% had terminated their employment, and 1% had died while still employed.
Follow-up for vital status was successful for 99% of the cohort, and there
were 3,198 deaths. Death certificates were procured for all but 25 (0.8%) of
the people in the cohort.
Eighty-five percent of the cohort were white males. The remaining 15%
was distributed as follows: 9% black males, 5% white females, and 1% black
females.
The total cohort had a statistically significant lower mortality than ex-
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pected for all causes of death (SMR = 91, observed = 3,198), mental disorders
(SMR * 40, observed = 6), diseases of the digestive system (SMR = 71, observed
= 93), and for all external causes (SMR = 56, observed = 111). There were
slight elevations in SMRs for benign/unspecified neoplasms (SMR = 132, p > 0.05)
and for diseases of the blood and blood-forming organs (SMR = 120, p > 0.05).
The SMR for mortality from all cancers also showed a statistically non-
significant deficit (SMR = 94). Deficits (p > 0.05) were also observed for
mortality from cancer of the lung, skin, and genitourinary organs, leukemia,
and lymphopoietic system cancer. There were six sites for which greater-than-
expected cancer mortality was observed, based on five or more deaths; these
sites Included liver/gall bladder/bile duct (SMR « 133), pancreas (SMR = 107),
bone/connective tissue/skin/breast (SMR = 119), kidney (SMR = 143), brain/CNS
(SMR = 115), and lymphosarcoma/reticulosarcoma (SMR = 114). None of these
elevated SMRs was statistically significant.
A subcohort of workers employed during the study period showed reduced
SMRs for all causes of death and for all cancers. These SMRs were 62 (observed
= 670) and 76 (observed = 183) (p < 0.05 for both), respectively. Four of six
causes of death that were elevated in the total cohort were also elevated for
this subgroup but were not statistically significant. These causes of death
Included cancer of the liver/gallbladder/bile duct (SMR = 139), kidney (SMR =
148), and brain/CNS (SMR = 130).
Analysis by latency in employees who had more than 15 years of employment
showed the same pattern as that for the total cohort. The SMR for all cancers
showed a significant deficit (SMR = 90, observed = 613, p < 0.05).
A total of 18,402 white males contributing 120,053 person-years showed SMR
deficits for all the cause-specific deaths considered.
For black males (2,026 contributing to 11,550.9 person-years), SMRs of 97
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(observed = 284) and 92 (observed = 54) were observed for all causes of death
and for mortality from all cancers, respectively. Increased SMRs were observed
for mortality from cancers of all the digestive organs (SMR = 131), stomach
(SMR = 159), large intestine (SMR = 116), pancreas (SMR = 182), diseases of the
circulatory system (SMR = 116), and diseases of the genitourinary system (SMR =
120). "All of these increases were statistically nonsignificant.
When data were analyzed by plant, cohorts from the Baton Rouge, Lousiana,
and Baytown, Texas, plants showed SMRs of less than 100 for all causes of
death. The only exception to this was an observed nonsignificant SMR increase
for symptoms/senility/i11-defined conditions in the Texas plant cohort and an
SMR of 100 for circulatory system diseases at the Baton Rouge plant.
The Bayway/Bayonne, New Jersey, plant cohort had an SMR of 100 for all
causes of death and a statistically significant excess in mortality from all
cancers (SMR = 116, observed = 259) and from endocrine/nutrition/metabolic
diseases (SMR = 148, observed = 32). Two nonsignificant increases in the SMR
were observed for diseases of the circulatory system (SMR = 106) and for symp-
i
toms/senility/i11-defined conditions (SMR = 135).
Further examination of cancer mortality in these three plants revealed SMR
deficits for the Baton Rouge (SMR = 92, observed = 249) and Baytown (SMR = 75,
observed = 158, p < 0.05) plant cohorts. There were statistically nonsignifi-
cant increases in the SMRs for pancreatic cancer (SMR = 152) among the Baton
Rouge cohort, kidney cancer for both the Baton Rouge (SMR = 155) and the Bay-
town (SMR = 123) cohorts, brain and CNS cancer for the Baytown cohort (SMR =
131), and for all lymphopoietic cancer (SMR = 108) for the Baton Rouge cohort.
The Bayway/Bayonne plant cohort had statistically significant (p < 0.05) in-
creases for all cancer deaths (SMR = 116, observed = 259) and for mortality
from cancer of the digestive organs (SMR = 132, observed = 84); mortality from
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respiratory system cancer was of borderline (p - 0.05) statistical significance.
The same cohort had no statistically significant SMR increases for the other
cancer sites considered.
When local, state, and county rates were applied to the statistically sig-
nificant cause-specific cancer mortality results for the Bayway/Bayonne plant,
such as all cancer deaths, cancer of the digestive system, and cancer of the „
respiratory system, these SMRs were reduced, leading the authors to the conclu-
sion that regional factors were affecting mortality from these causes.
This study is the first phase of a multiphase study. It has a short fol-
low-up period, although some retirees (who were alive on the starting date) were
included. No data on exposure to gasoline vapors or job titles were available.
The study sites also include chemical plants. A very weak analysis by latency
using the subcohort hired prior to 1956 is presented. The total cohort, in-
cluding both sexes and races, was analyzed as a homogeneous population, making
it difficult to draw any conclusions. Confounding factors are not taken into
consideration. Thus, this study is considered inadequate to use as a basis
from which to draw any conclusions with regard to gasoline exposure.
4.2,1.20. Han iset al. (1985bJ—This is the second part of a multi-objective
retrospective cohort mortality study of employees at three Exxon refineries and
chemical plants. The cohort of 21,698, contributing 137,702 person-years, was
observed from 1970 to 1977. The study design, cohort definition, and data
collection techniques, except for smoking history data, were handled in exactly
the same manner as those described in these authors' earlier (1985a) study.
Smoking histories were obtained from employee medical records kept since
the mid-1960s; however, "consistency of detail varied by plant." The measure
of smoking exposure was ever, never, or unknown. Histories were available for
7Q% of the cohort.
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To derive the occupation for which each employee had spent the largest
portion of his/her working time9 work histories were reviewed; 3% of these were
missing. Nine occupational categories were created for analyses: official/
manager, professional, technician, office worker/clerk, process operator,
mechanical worker, unskilled laborer, service worker, and laboratory techni-
cian/field professional. Job titles within each category were presented.
Occupational categories were further classified into two exposure groups. The
nonexposed group consisted of officials/managers, professionals, technicians,
and office workers/clerks. The remaining occupational categories were classi-
fied as potentially exposed to "petroleum, petrochemicals, and other related
substances."
The total study population was used as the standard population unless
otherwise specified. Age-, sex-, race-, and calendar year-specific death rates
in the subgroup of interest (e.g., smoking males) were multiplied by the number
of person-years in the appropriate cell in the standard population to obtain
directly adjusted death rates. The expected number of deaths resulting was
then summed over all the cells and divided by the total number of person-years
in the standard population, and then multiplied by 10,000 to yield the directly
adjusted rates per 10,000 person-years. ;The Mantel-Haenszel procedure was used
to test the rate ratios (relative risk) for statistical significance.
Thirty-three percent of the cohort were classified as mechanical workers,
28% as process operators, and 11% as professionals. Of the study population,
75% had potential for "daily exposures" to petroleum, petrochemicals, or other
related substances, 22% had "little" potential for exposure, and 3% had unknown
potential.
Analyses by mortality outcome, either a mortality rate or a rate ratio,
were presented by geographic site, occupational subgroup, and smoking category.
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Results were not reported for those cause-specific diseases in which there were
fewer than five observed deaths per geographic site or exposure group.
Mortality rates among plants were fairly consistent, and for all causes of
death were virtually identical. The only cause of death whose rates were high-
er than those of the U.S. population for all three plant cohorts was kidney
cancer; the highest rate ratio (HRR), ratio of the highest plant mortality rate
to the U.S. rate observed, was 1.5 (observed = 9, i.e., number of observed
deaths at the plant with the highest mortality). Pancreatic cancer rates were
higher than U.S. rates at the Baton Rouge and Baytown plants (HRR = 1.7,
observed =23). Rates at the Bayway/Bayonne plant for cancers of the stomach
(HRR = 1.1, observed =16), large intestine (HRR = 1.3, observed - 32), and
lung (HRR = 1.1, observed = 77) were slightly higher than the U.S. rates.
Mortality rates for endocrine/nutritional/metabolic diseases were higher at
the Baytown and Bayway/Bayonne plants in comparison to the U.S. rates (HRR =
1.7, observed =* 9). At all three plants, mortality rates for diseases of the
respiratory system (HRR = 0.9, observed = 48) were lower than the U.S. rates.
Mortality rates of the potentially exposed group were generally higher
than those of the nonexposed group, and for all causes of death a significant
(p < 0.05) rate ratio of 1.2 was observed. Elevated (p > 0.05) over those
of the nonexposed group were mortality rates of the potentially exposed for
all malignant neoplasms (RR = 1.2) and cancers of the digestive system (RR =
1.4), pancreas (RR = 1.1), lung (RR » 1.3), genitourinary organs (RR = 1.6),
and prostate (RR = 1.9). Mortality rates for cancer of the brain/CNS (RR =
0.3), respiratory system diseases (RR = 0.7), and digestive system diseases
(RR =* 0.8) were all lower (p > 0.05) than the U.S. rates. Also significantly
elevated was the rate ratio for diseases of the circulatory system (RR = 1.4).
Directly adjusted mortality rates were also presented for the nine occu-
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pational categories for selected causes of death. The nonexposed technicans
had the highest rates for all causes of death and for all cancers. The exposed
laborers had the second highest rates for all causes of death and for all can-
cers. A consistent pattern could not be discerned for specific cancers, and
only limited data were presented. However, mortality rates for mechanical
workers (MR/10,000) for kidney cancer were approximately 45% higher than the
U.S. rates (MR » 1.6 vs. MR = 1.1).
As part of this review, all job titles and occupational categories (as
presented by Hanis et al.) were rereviewed by a certified industrial hygien-
ist to identify those job titles and occupational categories that would have
employees with potential gasoline exposure. The occupational category of
laboratory technician/field professional (N = 909) was identified as contain-
ing workers exposed to gasoline during the sampling and testing of gasoline in
the quality control laboratories. The laborer category (N = 1,572) contained
workers who were potentially exposed to gasoline during transport loading
operations or during maintenance activities. The process operators category
(N = 6,135) contained process operators and technicians who may be exposed
to gasoline during sampling procedures. All three of these categories were
classified by the authors as potentially exposed to petroleum, petrochemicals,
or other related substances.
A review of the authors' data by occupational category indicated that
directly adjusted mortality rates for laborers (MR = 56) and processors (MR
= 53) were only slightly higher than U.S. rates (MR = 51) for all cancers.
Lung cancer mortality rates for laborers (MR = 16.4), processors (MR = 18.9),
and laboratory technicians (MR = 18.6) were higher than U.S. rates (MR = 16.0).
Digestive system cancer rates for laborers (MR * 16.1) and processors (MR =
18.3) were also higher than the U.S. rates (MR - 14.2).
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Smokers were generally observed to have a higher risk of death when com-
pared to nonsmokers. Significant (p < 0.05) rate ratios for all causes of
death (RR = 1.9) and all cancer deaths (RR = 2.3) were observed. An elevated
rate ratio was observed for smoking exposure for all digestive organ cancers
(RR s 1.6). Conversely, smokers were at reduced risk for cancers of the pan- ,
creas (RR = 0.8), genitourinary organs (RR = 0.9), and prostate (RR = 0.6).
Rate ratios for other malignant neoplasms were not presented.
The authors further examined the relationship of smoking to refinery expo-
sure by post-stratifying smoking exposure (ever/never) by occupational catego-
ries (potentially exposed to petroleum products/not exposed). Smokers were
observed to be at increased risk of death when compared to nonsmokers regard-
less of refinery exposure. The only exception was for cancer of the pancreasj
smokers potentially exposed to refinery products were at reduced risk of death
compared to nonsmokers (RR = 0.8).
Occupational exposures were then stratified by smoking categories. The
risk of death among smokers potentially exposed to refinery products was always
greater than among those not exposed to refinery products. Significant (p < ,
0.05) rate ratios were observed for all causes of death (RR = 1.2) and diseases
of the circulatory system (RR = 1.4). Risks for all malignant neoplasms (RR =
1.2) and cancers of the digestive organs (RR = 1.2) and respiratory system (RR
- 1.7) were also elevated among smokers.
Detailed results were not presented for the nonsmoking population; how-
ever, the risks for those potentially exposed to refinery products were slight-
ly elevated over the nonexposed group for all malignant neoplasms (RR = 1.2).
The pancreatic cancer mortality rate among the potentially exposed nonsmokers
was higher (MR = 4.8) than the rate among the two smoking groups (MR = 4.8 vs.
3.4).
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This study has many of the same limitations as the authors' earlier study
(1985a), There was a lack of information on gasoline exposure. The follow-
up period was short. No latency analyses were Included. The study sites
also Included chemical plants, and the only confounding factor taken Into con-
sideration was smoking. Smoking information was missing for 30% of the cohort.
Since smoking is associated with both the outcome variable (mortality) and
exposure (smoking is generally prohibited in certain areas of the plant), a
selection bias 1s potentially Introduced into the analysis of the smoking
data. In addition, the authors presented no data with which to evaluate dose-
response effects. This is unfortunate, as this is one of the few studies
where,, because mortality rates were adjusted by the direct method rather than
by the indirect method used to calculate SMRs, subcohort risks could be direct-
ly compared. ,
Based on the above-mentioned reasons, this study provides insufficient
evidence for the carcinogenicity of gasoline vapors.
4.2.1,21. Divine et al. (1985)—This is a retrospective cohort study consist-
ing of 19,077 white male employees of Texaco, Inc., who worked for a minimum of
5 years prior to December 31, 1977, at refinery, petrochemical, and research
facilities owned by the company; at least 1 day of employment had to occur be-
tween January 1, 1947, and December 31, 1977. There were 358,029 person-years
of observation. Employees who transferred from other company facilities could
not be identified. Excluded from the cohort were employees of the administra-
tive, engineering, and medical services departments, and employees of a former
subsidiary who terminated employment before 1955;
Data on the employees, obtained from company records or the SSA, included
employee's name, social security number, race, sex, date of birth, and a com-
plete occupational history, when available.
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Of the 19,077 white males Included 1n the study, 4,024 (21.1%) were de-
ceased as of December 31, 1977. The vital status of 444 (2.3%) of the employ-
ees was unknown. Death certificates were obtained for 3,872 (96.2%) of the
decedents from company records or state vital statistics departments.
The underlying cause of death was receded by a trained nosologlst accord-
Ing to the 7th revision of the ICD, SMRs were calculated by using the U.S.,
white male population as the comparison group (Monson, 1974). Ninety-five
percent confidence intervals were also calculated. The calculation for the
overall SMR included the decedents for whom no death certificates were recov-
ered; cause-specific SMRs were calculated without using these decedents. Those
lost to follow-up were assumed lost on the date of last employment.
The overall SMR was 75 (4,024 deaths observed, p < 0.05). In most major
cause of death categories, the SMR was significantly (p < 0.05) less than unity
(100), including all malignant neoplasms (SMR = 75, observed - 767) and cancers
of the digestive organs (SMR = 70, observed = 215), stomach (SMR = 70, observed
= 45), large intestine (SMR = 68), observed = 64), lung (SMR = 59, observed =
182), and bladder (SMR = 56, observed = 19), The SMR for benign neoplasms was
148 (20 deaths observed, p > 0.05), which was the highest SMR observed. The
elevated cancer SMRs were for cancers of the pancreas (SMR = 107, observed -
62, 95% CI 82-138), brain (SMR « 111, observed = 31, 95% CI 75-157), and for
Hodgkin's disease (SMR 108, observed = 13, 95% CI 58-185), leukemia (SMR =
118, observed = 48, 95% CI 87-156), and cancer of other lymphatic tissue (SMR
- 115, observed = 25, 95% CI 74-170). Significantly (p < 0.05) reduced SMRs
were observed for all non-cancer causes except benign neoplasms (endocrine
and metabolic diseases SMR = 78, observed = 78; vascular lesions of the CNS
SMR = 79, observed = 322; diseases of the circulatory system SMR =79, observed
s 1,975; arteriosclerotic heart disease SMR = 81, observed = 1,623; respiratory
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diseases SMR = 52, observed = 159; emphysema SMR = 60, observed = 52; diseases
of the digestive system SMR = 56, observed = 141; cirrhosis of the liver SMR
= 47, observed 56; diseases of the genitourinary system SMR = 53, observed =
43; external causes of death SMR = 54, observed = 227; and accidents SMR = 53,
observed = 152).
It is difficult to draw conclusions from this study. Although the study
population is quite large and covers an appreciable period of time, 30 years,
job-specific data were not included, which makes exposure assessment difficult.
The cohort consisted of employees who worked at "the refinery, petrochemical,
and research facilities"; these and other confounding factors (e.g., smoking)
were not controlled for. The authors failed to state that ,the calculations of
their SMRs were time-specific; however, the Monson program will calculate time-
specific SMRs if instructed to do so.
The lack of information on length of employment, latency, or type of expo-
sure makes this study insufficient for forming conclusions as to an association
between gasoline and cancer,
4.2.1.22. Barron and Divine (1985)--At a 1985 meeting of the Society for
Epidemiologic Research, Barron and Divine presented preliminary results from
a nested case-control study using the cohort studied by Divine et al. (1985).
Cases consisted of 31 white male employees with cancer of the brain and 12 with
benign and unspecified tumors of the brain. Controls (four per case) were
matched for age and date of hire. Significant rate ratios were found in two
work areas: research laboratories and lube oil refining units when comparing
those ever employed to those never employed. Specific odds ratios and p values
were not reported. For cases4 the average employment duration in the work area
was 5 years longer than controls in the laboratory and 2 years shorter in lube
oil refining. The authors reported that employment histories of cases in the
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laboratory setting appeared to be concentrated in the 1940s. No additional
details were presented.
The lack of any information on control selection, case verification, or
details on the magnitude of the risk preclude using this study as a basis for
forming conclusions as to an association between gasoline and primary brain
cancer.
4.2.1.23. Nelson (1985 Unpublished)—This is a retrospective cohort mortality
study of Amoco Oil refinery employees from 10 geographically dispersed U.S.
refineries that used generalized processes to produce a variety of petroleum
products, including unleaded gasoline. The cohort of 10,763 individuals
(104,954 person-years of follow-up) consisted of all full-time regular employ-
ees who worked in one of the refineries for at least 6 months, at least 1 day
of which was between January 1, 1970, and December 31, 1980.
The vital status of each cohort member was assessed as of December 31,
1982, through the SSA, the National Death Index, or company records. The com-
pleteness of the cohort was verified against Social Security 941 forms. Only
2.1% of the cohort members (1.5% of the white males) were lost to follow-up.
Death certificates were obtained for 971 of the 983 decedents from company
files or from the appropriate state's records of its vital statistics depart-
ment. The underlying cause of death was coded by an experienced nosologist to
the 8th revision of the ICD.
Information on cohort members was extracted from computerized company work
records and included social security number, name, sex, race, birth date, em-
ployment type (salaried or "ever hourly"), hire date, termination date, and
refinery where employed. Smoking information was available for 59% of the
total cohort (i.e., those individuals who had company-sponsored medical exam-
inations from 1976 to 1982). However„ this information was not available for
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90% of the decedents.
Computerized job history Information was used to group cohort members
by exposure categories. "Most frequent" job title and in-plant locations
were assumed to be representative of a worker's entire employment history,
A validation study of this method was conducted in the Salt Lake Refinery
(N = 387) where the author found that "most frequent computerized job title
was . . . representative of an employee's complete job history approximately
89% of the time."
Four mutually exclusive exposure groups were established: (1) job type
(administrative, maintenance, operations, and unknown), (2) contact with refin-
ery products, (3) contact with light aromatic hydrocarbons (benzene, toluene,
xylene), and (4) contact with heavy oils (catalytically cracked oil or coker
gas oil). The latter three exposure groups were categorized as none, occasion-
al, routine, and unknown. Cohort members were categorized into exposure cate-
gories by an industrial hygienist, using the most frequent job title and loca-
tion information. The exposure category selection process was based on a
qualitative evaluation of job categories.
SMRs were calculated using the Honson program (Monson, 1974) updated
through 1980, which compares observed deaths to those expected based on U.S.
death rates. SMRs and two-sided 95% confidence intervals were calculated by
race and sex for 42 selected causes of death.
White males comprised 85.4% of the cohort; black males, white females, and
black females comprised 8.2, 5.4, and 1%, respectively. The majority of the
cohort members (66%) were employed at the Whiting and Texas City refineries.
Over half (51%) of the employees were employed by the company for 25 years or
more; 37% were employed for 9 years or less.
Among the white male cohort members, the SMRs for all causes of death (SMR
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= 73, observed = 921) and all cancer deaths (SMR = 84, observed = 259) were
reduced significantly (p < O.Oi). Conversely, a significantly elevated (p <
0.05) SMR of 201 was observed for skin cancer (observed =11), Elevated (but
not significantly) were cancers of the rectum (SMR = 149) and stomach (SMR -
148). SMRs were slightly elevated for cancers of the large intestine (SMR =
113), liver (SMR = 116), pancreas (SMR = 110), and bladder (SMR = 109). The
SMR for benign neoplasms (SMR = 178) was also elevated. Statistically signif-
icant deficits were observed for several causes of death, including cancers of
the buccal cavity and pharynx (SMR = 20, observed = 2) and lung (SMR - 63, ob-
served =75); lymphatic and hematopoietic tissue cancers (SMR = 60, observed
s 16); and diseases of the circulatory system (SMR = 75, observed = 461,
norwmlignant respiratory system (SMR = 50, observed = 38), digestive system
(SMR =* 60, observed = 39), and genitourinary system (SMR = 38, observed = 4);
and accidents, poisonings, and violence (SMR = 53, observed = 55).
The SMR among black males for all causes of death (SMR = 68, observed
= 50) was significantly reduced. Nonsignificant increases in the SMR were
observed for cancers of the large Intestine (SMR » 224), kidney (SMR = 443),
and bra1n/CNS (SMR - 510); however, these SMRs were based on only one or two
observations.
Among white females, the SMR was depressed for all causes of death (SMR =
69) and elevated for cancers of the large intestine (SMR = 178, observed = 1),
liver (SMR = 902, observed =1), and diseases of the circulatory system (SMR -
114). None of these SMRs was significant. No deaths occurred among the black
female cohort members.
Subcohort analyses were limited to white males. Statistically signifi-
cant elevated SMRs for digestive system (SMR = 137, observed = 49) and stomach
cancer (SMR = 207, observed =11) were observed among white males employed at
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the Whiting, Indiana, refinery and among all white cohort males hired before
**.
1940 (digestive cancer SMR <= 163, observed = 36; stomach cancer SMR = 243,
observed =8). A statistically significant SMR for digestive system cancer
(SMR = 139, observed = 53) was also observed among those who were routinely
exposed to light aromatic hydrocarbons.
Statistically significant elevations in the skin cancer SMR were found.
among several subcohorts. All of those who died of skin cancer (observed = 11)
were ever-hourly employees (SMR = 263) and tended to be maintenance workers
(SMR = 378, observed = 8) who were routinely exposed to refinery products (SMR
= 268, observed = 10), light aromatic hydrocarbons (SMR = 262, observed =7),
or heavy oils (SMR = 259, observed =7). Others at risk for skin cancer were
those hired after 1945 (SMR = 292, observed =8) and those with less than 15
years of latency (SMR = 524, observed =3).
SMRs were elevated, although not significantly, for cancers of the rectum
and liver among maintenance workers; ever-hourly employees; those who were ex-
posed (occasionally or routinely) to refinery products, light aromatic hydro-
carbons, or heavy oils; those hired before 1940; and those with 15 years or
more of latency. Elevated kidney cancer SMRs were observed among salaried
employees; administrators; those with no exposure to refinery products, light
aromatic hydrocarbons, or heavy oils; and those hired before 1940.
SMRs for all causes of death, by refinery, were also calculated using
state and county death rates as the standard. SMRs for 7 of 10 refineries were
slightly lower than U.S.-based rates. For example, the SMR based on U.S. rates
for all causes of death at the Whiting refinery was 81 versus an SMR of 77
based on state Crates. County-based rates were slightly lower than state rates,
the SMR for all causes of death at Whiting equaling 74. SMRs, using county
mortality rates as the expected rates, were also calculated for selected causes
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of cancer death. The overall pattern of risk remained unchanged—those causes
of death with elevated rates continued to exhibit similar patterns of excess
risk. Noticeable differences were observed among Whiting employees whose cause
of death was malignant melanoma of the skin (SMR = 213 based on U.S. rates ver-
sus SMR » 267 based on county rates).
The author also calculated, by the direct method, the SMRs for all causes
of death and all cancer deaths to examine dose-response effects of white male
exposure to refinery processes, light aromatics, or heavy oils. The relation-
ship among rates standardized to the U.S. rates were similar to those based
on rates standardized to the study population. There appeared to be a dose-
response effect for all causes of death for the three exposure categories.
Patterns for all cancer deaths were not so clear-cut. Among those with occa-
sional exposure to refinery processes, the risks appear to be less in compari-
son to those with no exposure, whereas among those occasionally exposed to
heavy oils, the risks appear to be greater than those of the nonexposed or rou-
tinely exposed groups.
There are several limitations to this study with regard to evaluation of
gasoline exposure. The main limitations are the lack of information on gaso-
line vapor exposures and the fact that products other than gasoline were rou-
tinely manufactured in all the refineries. For example, four of the refineries,
representing 77% of the study population, also manufactured petroleum coke.
Also, there was some redundancy among the four exposure groups. For example,
43% of the total cohort was routinely exposed to light aromatics and heavy oils
(Nelson et al., 1985). There was no control during these analyses for these
multiple exposures.
Results were not consistent among-refineries. For example, excess stom-
ach cancer was observed at five of the seven refineries for which deaths were
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observed; at the Whiting refinery (N = 3,474) there were significant elevations
{SMR = 207), whereas at the Texas City refinery (N » 2,472) a deficit (SMR -
48) was observed.
There was excellent follow-up; however, the period of follow-up was short.
This is especially important considering that one-third of the study population
were employed for less than 9 years (10 to 30 years generally being the latency
for environmental carcinogenesis).
Finally, confounding factors such as smoking were not taken into consi-
deration. Thus, this study provides insufficient evidence for the carcino-
genicity of gasoline vapors.
4.2.2. Case-Control Studies that Evaluated Employmentinthe Petroleum Industry
asa Risk Factor
4.2.2.1. Cole et al. (1972)—During an 18-month period, Cole et al. (1972)
attempted to identify all residents, ages 20 to 89, with newly diagnosed blad-
der cancer in eastern Massachusetts, including Boston. Six hundred and sixty-
eight cases were identified that included transitional or squamous-cell malig-
nancies of the renal pelvis, ureter, bladder, or urethra. Of these, a random
sample of 510 was selected for interview, and usable occupational interviews
were obtained for 461 cases (356 males, 105 females). Controls were selected
from the age- and sex-stratified sample of the adult population of the study
area and matched for sex and year of birth. Of 668 persons initially identi-
fied as potential controls, 485 (374 males, 111 females) provided usable occu-
pational histories.
Questionnaires administered to both cases and controls provided detailed
information on occupational history. Occupations were classified according to
occupational exposures and occupation titles. Based on a literature review, 13
occupational categories were created and ranked from "presumed highest risk of
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bladder cancer" (dyestuffs manufacture and use) to lowest (office workers),
based on "similar" exposures. The suspect category, rankings 1 to 8, Included
dyestuffs, rubber, leather, printing, painting, petroleum, organic chemicals,
and other chemicals, respectively. The nonsuspect category, rankings 9 to 13,
Included fumes and smoke, manufacturing not elsewhere classified, ranching and
farming, service occupations, and office work, respectively. The category
involving petroleum products was ranked 6, a suspect category.
Occupations were also classified according to job titles. This was done,
according to the authors, in order to look for previously unrecognized hazard-
ous occupations. Occupations were assigned title codes based on description of
work alone, without regard to exposure. From the detailed work histories, each
person was assigned up to nine occupations.
Relative risks were calculated from observed number of cases and expected
number of cases. Expected numbers of cases were calculated based on the fre-
quency distribution of the control's occupational categories. All risk esti-
mates were controlled for age (20 to 59, 60 to 74, and 75 to 89). To evaluate
the association between occupation and cigarette smoking, risk estimates were
controlled for smoking using three categories of maximum daily cigarette con-
sumption: nonsmokers, up to one-half pack a day, and more than one-half pack a
day. Relative risks and their associated 95% confidence limits were calculated
by Sheehe's modification (1966) of Woolf's technique. This may, according to
the authors, result in conservative estimates of relative risk.
Risk estimates were presented comparing cases to controls for each of the
suspect exposure categories. All risks were calculated relative to the non-
suspect categories. Estimates based upon the total number of cases and con-
trols occurring 1n each of the 13 categories were calculated controlling for
age and smoking. In total, the case population contributed 1,241 different
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observations (i.e., occupations).
Significantly (p < 0.05) elevated relative risks of 1.57 (95% CI 1.04-
2.36) and 2.00 (95% CI 1.37-2.90) were observed for the rubber and leather
occupational categories, respectively. The relative risk for petroleum product
occupations was 1.00, showing no increase or decrease in risk.
When the cases were classified according to the single mutually exclusive
category of "usual occupational exposure," results were similar to those cited
above. Increased relative risks were seen for rubber, leather, paint, and
other organic chemical occupations, though none of these was significantly dif-
ferent than for the nonsuspect workers. The relative risk for petroleum occu-
pations was 1.05 (95% CI 0.65-1.71). These risks are age-adjusted only.
Cases were also classified according to whether or not they were "ever
employed" 1n each of the suspect categories. When controlled for age and smok-
ing, increased risks were observed for all suspect categories except "other
chemicals." Significant (p < 0.05) Increases were seen for the rubber and
leather categories, with relative risks of 1.63 (95% CI 1.04-2.56) and 2.25
(95% CI 1.46-3.46), respectively. The relative risk for the petroleum category
was 1.18 (95% CI 0.82-1.69). This was not significant.
The authors discussed an interesting feature of the petroleum exposure
category. It is the largest of the eight suspect categories in that more of
the cases were classified as ever working in the petroleum Industry. One sub-
category, machinists and mechanics, accounts for 81% of the observations in the
petroleum category (RR - 0.92 for this subgroup). When this group is excluded,
other petroleum work has a relative risk of 1.61 (95% CI 0.932.79), although
this is not significant. Not reported was whether this risk estimate was ad-
justed for age and/or smoking.
The data were also studied with respect to occupation title. It could not
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be determined if the authors' categorization by job title was for "usual job
title" or "ever employed" in a particular job title. Relative risk estimates
by job title were similar to those seen for "usual" occupation for those em-
ployed in the rubber, leather, and paint industries; however, none of these
risks was statistically significant. Petroleum work showed no increase
in risk, exhibiting a relative risk of 0.96. The authors stated that for
petroleum work, as in the earlier analysis, the nonsignificant relative risk
may mask increased risk within subgroups. This, however, is not investigated
in more detail.
This study failed to established a link between bladder cancer and petro-
leum work when based on a classification of occupation according to either a
priori exposure categories or job title classifications. By the authors' own
admission, individuals identified as petroleum workers made up a large portion
of the study population; further analysis by subgroups may have been warranted,
but no data were presented. The authors do suggest that certain subgroups of
bladder cancer cases may have increased risk if they worked in the petroleum
industry, but specific job classifications or exposure history, duration, or
concentrations were not presented, although this information may have been
available through the detailed occupational history questionnaires. Thus, this
study is Inadequate to link gasoline exposure or refinery exposure to bladder
cancer.
4.2.2.2. Howe et al. (1980)—The authors conducted a population-based case-
control study of bladder cancer in the Canadian provinces of British Columbia,
Newfoundland, and Nova Scotia. Cases were identified through the population-
based cancer registry for each province; they were identified as all patients
with newly diagnosed bladder cancer occurring between April 1974 and June 1976.
Interviews were obtained for 77% of the cases identified. Neighborhood controls
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were Individually matched to the cases on the basis of sex and age (+_ 5 years).
The authors reported that 20% of the potentially eligible controls In British
Columbia refused to be Interviewed, as did 4% 1n Nova Scotia; all potential
controls were interviewed in Newfoundland, The final study population con-
sisted of 480 pairs of males and 152 pairs of females.
Subjects were interviewed 1n their homes. Respondents provided details
on their smoking practices, employment history, occupational exposures, use of
hair dyes and analgesics, beverage consumption patterns, history of kidney and
bladder conditions, and consumption of possible nitrite sources in their diet.
Information was also obtained on the use of artificial sweeteners; these re-
sults were reported elsewhere (Miller and Howe, 1977; Howe et a!., 1977).
A matched analysis with the linear logistic model (Breslow et al.» 1978)
was used to assess relative risk. Two-sided 95% confidence intervals were
calculated for the risk estimates. Tests of significance and interval estima-
tion were based on the binomial distribution (Miettinen, 1970). The Mantel
extension procedure was used to test for trend (Mantel, 1963).
Fourteen industries or occupations were considered a priori as high-risk
industries; the petroleum industry was one of these. The male cases were 5.3
times more likely than their controls to have ever been employed in the petro-
leum industry (95% C! 1.5-28.6). Employment 1n the chemical industry was also
found to be a significant risk factor (RR = 7.5, 95% CI 1.7-67.6). Elevated,
though not significantly, were the rubber (RR = 5.0), photographic (RR = 3.0),
medicine (RR = 2.6), and food processing (RR = 1.6) industries; the authors
subsequently treated these as high-risk Industries for males. Risks were also
elevated (p > 0.05) for males employed in the cloth dyeing (RR = 2.0), tanning
(RR = 1.2), and tailoring (RR = 1.5) industries; however, the authors did not
subsequently treat these industries as high-risk industries, probably because
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of the small numbers of exposed males. All of these estimates remained "un-
changed" after controlling for cigarette smoking,
The risk for subjects who reported exposure to dust and fumes in other
industries was observed at a significant 2.5 for males (95% CI 1.8-3.6) and
a nonsignificant 4.5 for females. These estimates were not affected by those
who reported working in the a priori high-risk industries. Dust exposures
were then regrouped into four subcategories based on "logical groupings of
similar fumes or dusts." The risk for diesel and traffic fume exposure was
elevated (RR = 2.8), although not significantly. Exposures to welding fumes
(RR = 2.8, 95% CI 1.1-8.8) and railroad dust and fumes (RR = 9.0, 95% CI 1.2-
394,5) were both significantly elevated. Exposure to crop spraying was reported
by the authors as significantly elevated (RR - 7.0, p < 0.05), but the confidence
interval included 1 (95% CI 0.9-315.5).
The authors also examined occupational exposures for males by considering
specific job titles that were coded to the 4-dig1t 1971 Canadian census code.
Risks were elevated for the following job titles: guards and watchmen (RR =
4.0, 95% CI 1.3-16.4), nurserymen (RR = 5.5, 95% CI 1.2-51.1), metal machinists
(RR - 2.7, 95% CI 1.1-7.6), and material recorders (RR = 2.6, 95% CI 1.0-7.3).
Elevated (p > 0.05) were risks for glass processors (RR = 6.0) and mechanics
(RR =1.6). All of these risks remained unchanged after controlling for cig-
arette smoking, whereas risks for those in the armed services (RR = 1.4) or
those employed as clerical workers (RR = 1*4) were reduced to statistically
nonsignificant excesses after controlling for smoking.
Male study subjects responded positively to only two chemicals listed on
the questionnaire: benzidine and its salts and bis(chloromethyl)ether. Though
elevated (RR = 1.3 and RR = 5.0, respectively), risks for exposure to these
substances were not observed at significant levels.
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Age (< 60, _>. 60) appeared to confound the results for males exposed to an
a priori high-risk industry. Risk for the Individuals less than 60 years of
age and exposed to an a priori high-risk industry was more than four times (RR
= 8.5, 95% CI 2.0-75.8) that for individuals ages 60 and above (RR = 2.1, 951
CI 1.1-4.2) who were also exposed to an a priori industry. Age appeared not
to confound the risks for exposure to dust or fumes.
Bladder cancer risks were elevated for females employed in tailoring (RR
- 2.0), medicine (RR = 1.2), and for clerical occupations (RR = 1.3); however,
these elevated risks were not statistically significant.
For both sexes, a statistically significant (p < 0.01) dose-response rela-
tionship was observed for cigarette smoking, measured as average frequency of
cigarettes smoked per day and categorized as more than 0 to 10 cigarettes (RR
» 2.6, 95% CI 1.7-4.4), 10 to 20 cigarettes (RR - 3.8, 95% CI 2.6-6.0), and
more than 20 cigarettes (RR = 5.1, 95% CI 3.5-8.6) per day. A similar dose-
response relationship (p < 0.01) was observed for duration of cigarette smoking
(up to 20 years: RR » 1.8, 95% CI 1.1-3.3; 21 to 40 years: RR ~ 3.9, 95% CI
2.6-6.4; and greater than 40 years: RR = 4.8, 95% CI 3.3-7.7) and total life-
time consumption of cigarette packs (up to 10,000 packs: RR = 2.5, 95% CI
1.7-4.0; 10,000 to 20,000 packs: RR * 4.4, 95% CI 3.0-7..2; and more than
20,000 packs: RR • 5.8, 95% CI 3.9-10.3).
Risks were also assessed for consumption of coffee (regular or instant),
tea, alcohol, non-diet colas, other non-diet soft drinks, and diet drinks. The
only excesses observed among males were for those who consumed regular coffee
(RR = 1.5, 95% CI 1.0-2.2) or instant coffee (RR = 1.5, 95% CI 1.2-2.0). No
statistically significant findings were reported among the female group, though
risks for subjects who consumed non-diet colas (RR = 2.0) and instant coffee
(RR = 1.4) were elevated.
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Statistically significant risks were also observed for males who were
users of non-public water supplies (i.e., "a source of higher than average
quantities of nitrates and nitrites"), but there was no dose-response rela-
tionship observed (_< 10 years of exposure: RR = 2.2, 95% CI 1.5-3.6; 10 to 20
years: RR * 1.9, 95% CI 1.2-3.2; > 20 years: RR « 2.1, 95% CI 1.5-3.2). No
increase 1n risk among males or females was observed for consumption of preser-
vative-containing meats or flddlehead greens (i.e., a green similar to bracken
ferns, a bladder carcinogen in cows).
Both males and females had an excess risk (p values and CIs not reported)
for conditions of the kidney or bladder that occurred up to 5 years prior to
diagnosis (male bladder conditions, RR = 4.9; female bladder conditions, RR
- 2.8). Analgesics containing aspirin were observed to be a significant risk
factor for males (RR =1.5, 95% CI 1.0-2.3). Analgesics appeared not to be a
risk factor for females. Significantly (p = 0.004) more male cases than male
controls (8 cases, 0 controls) reported using hair dyes; relative risk esti-?
mates were not reported. No increase 1n risk was observed for females (RR =
0.7, 95% CI 0.3-1.4) who used hair dyes.
The authors used the linear logistic model (logistic regression) to assess
the simultaneous effects of smoking, occupational exposures, and other vari-
ables of interest. For males, the effects of cigarette and pipe smoking,
occupational exposures, use of non-public water supplies, and grades of school
"were very similar" to the univariate analysis; however, occupational exposures
were measured as exposure to any of the six a priori high-risk industries
rather than exposure to just the petroleum industry.
In conclusion, the authors reported that male bladder cancer cases who
worked in the petroleum industry were at si nificantly high risk (RR = 5.3, 95%
CI 1.5-28.6) and that this estimate remained unchanged after controlling for
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the confounding effects of cigarette smoking. They did not present an estimate
of relative risk for males employed In the petroleum Industry while simultane-
ously controlling for significant risk factors other than smoking (i.e., coffee,
artificial sweeteners, use of non-public water supplies, aspirin, other high-
risk industries, and dust and fumes); however, since the size of the risk
estimate for males in the petroleum industry, while controlling for smoking, is
approximately three times more than the univariate risk estimates for these
other risk factors, it can be inferred that risk in the petroleum industry
would still be elevated after adjusting for these other risk factors.
The paper suggests that the authors modeled the probability of bladder
cancer rather than modeling the probability of exposure, since they reported
their risk estimates as relative risks (the method used to calculate risk in a
prospective study) rather than as odds ratios (the method used to estimate risk
in a case-control study). If this assumption is true, it is not possible to
estimate the magnitude of risk for exposure to petroleum products given the
available data. In addition, it was not possible to determine if the individ-
uals in the petroleum industry were specifically exposed to gasoline, since
specific job titles were not presented. No information was presented on
duration of employment or latency. This study provides weak evidence of an
association between bladder cancer and employment in the petroleum industry.
4.2.2.3. Bladder Cancer Mortality Studies in Louisiana
4.2.2.3.1. Gottlieb and Pickle (1981). Gottlieb and Pickle (1981) conducted a
case-control study of urinary bladder cancer in Louisiana. Death certificates
were collected for all deaths attributed to bladder cancer from 1960 to 1975 in
19 parishes. Decedent controls were matched to the cases on the basis of sex,
race, parish of residence, and age (within 5 years), excluding those whose
cause of death was bladder cancer. This resulted in 347 bladder cancer cases
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(176 white males, 62 white females, 61 black males, and 48 black females) and
an equal number of matched controls. The objective of the study was to deter-
mine possible occupational, environmental, or ethnic influences on mortality
from bladder cancer in Louisiana.
Information on occupation and employment industry was abstracted from each
death certificate and coded according to the three-digit industries and occupa-
tion classification of the U.S. Bureau of the Census. The "usual" residence
listed on the death certificate was used to classify each individual as to
proximity to possible industrial sources. In addition, each individual was
assigned an Acadian ancestry code based on parent's last name and whether or
not his/her birthplace was in "Acadiana," a band of counties in southern
Louisiana. The authors stated that Acadians were of interest because they are
thought to be highly intermarried and thus represent a stable population.
Crude odds ratios were calculated for race, sex, age (dichotomized at 63
years), and type of parish strata to estimate risk associated with usual occu-
pation and Acadian ancestry. Parish types were classified according to indus-
trial activities and included six parishes with wood or paper plants, nine
parishes with chemical industries, three parishes with oil refineries, and five
parishes classified as other. These total to more than 19, as some parishes
had more than one industrial activity. The authors presented no information on
the method used to calculate the crude odds ratio. However, a review of their
data indicated that two methods were used, that of Fleiss (1981) (i.e., ad/bc)
or that of Haldane (1955) (i.e., adding one-half to each cell). No rationale
is presented as to why two different methods were used. Confidence intervals
were not reported by the authors for crude odds ratios; however, they were
calculated (a = 0.05) as part of this review by Cornfield's method (1956).
Analysis also included logistic multiple regression, where there were suffi-
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cient numbers for each sex and race group. However, the results reviewed here
are for crude odds ratios, since logistic regression odds ratios were not pre-
sented for the variables of interest.
Results indicate that bladder cancer was more common in white males whose
usual industry of employment was the oil refining industry. The risk relative
to employment in other industries was reported as 4.46 (95% CI 0.73-63.9).
Further analysis of these workers showed a high relative risk that decreased
with age, but no values were reported. Of the seven workers in the oil refin-
ing industry, four of the cases and one control lived in the same parish and
all but one lived in the same zip code area.
When studying usual occupations, elevated bladder cancer risks were ob-
served for white male mechanics (OR = 3.07, 95% CI 0.55-23.83), black male
transport equipment operators (OR =3.10, 95% CI 0.28-244.35), and white male
transport equipment operators (OR * 2.06, 95% CI 0.63-7.09). Further analy-
sis of these data shows that of six white cases with occupations as mechanics,
one worked at an oil refinery, three were auto mechanics, and two were rail-
road mechanics. Of the 10 white and 3 black transport equipment operators, 9
were bus or truck drivers. Specific occupations of the other four were not
described by the authors.
When studied by residential proximity to Industries, elevated odds ratios
were seen for white males and females living near paper manufacturing (OR =
1.34, 95% CI 0.73-2.49) and oil refining (OR - 1.12, 95% CI 0.63-2.01) plants.
For black males and females, elevated odds ratios were also seen for those
living near paper manufacturing (OR = 1.48, 95% CI 0.57-4.03) and oil refining
(OR = 1.41, 95% CI 0.20-X) plants. None of these elevated risks was signifi-
cant.
There are limitations to this study. Death-certificate studies are inher-
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ently limited in the conclusions that can be drawn from them. Occupational and
cause-of-death information is subject to misclassification bias. For example,
occupational information may be subject to a recall bias on the part of the
next-of-kin supplying the death certificate information. Inaccuracies inher-
ent in death certificate diagnoses of cancer are well documented (Percy et al.,
1981; Cope!and et al., 1977). Usually no information is available on length of
employment, and hence analyses by length of employment and latency are not
possible. Information on confounding variables such as cigarette smoking did
not exist on the death certificate and cannot be controlled for. The authors
calculated odds ratios for different groups by different methods. Thus, it is
not possible to directly compare results between different groups of workers.
Another limitation to this study is that reported results were not adjusted for
age, a confounding factor that could have been controlled for. There was no
control for exposure to other petroleum products. In addition, bladder cancer
does not always result in a mortality; therefore, the results of this study are
not comparable to studies of bladder cancer incidence. Finally, this study is
limited in its documentation of gasoline exposure. Thus, this study is inade-
quate for determining an association between gasoline and bladder cancer.
4.2.2.3.2. Gottlieb and Carr (1981). Gottlieb and Carr (1981) described the
results of several death certificate case-control studies in Louisiana that
investigated the occurrence of cancers of the lung, pancreas, bladder, and
other sites. Because of the heavy influx of petroleum refining, chemical,
and petrochemical industries in parishes along the Mississippi, the possible
contributions of these industries to cancer mortality were studied. The first
study involved a survey of death certificates for lung, pancreas, and bladder
cancer deaths for 1960-75 in 19 parishes of Louisiana. The second study,
which was expanded/to include cancers of the brain, kidney, and esophagus and
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leukemia, was designed to study the Influence of the source of drinking water
on cancer mortality. Reviewed here are the results of the bladder cancer
study. The pancreatic cancer data are presented later under the heading Pan-
creatic Cancer Mortality Studies in Louisiana. Likewise, the lung cancer data
are presented under the heading Lung Cancer Mortality Studies in Louisiana.
The data on brain, kidney, and esophageal cancers and leukemia are presented
under the heading Other Cancer Mortality Studies in Louisiana.
Data from the principal Investigators' previous bladder cancer case-con-
trol study (Gottlieb and Pickle, 1981) were used for additional analyses; the
reanalyses (Gottlieb and Carr, 1981) are reviewed here.
Odds ratios were recalculated for white male oil refinery workers. Risks
were relative to those not employed as oil refinery workers. Gottlieb and
Pickle (1981) originally reported an odds ratio of 4.46 (6 of 176 cases were
exposed and 1 of 176 controls were exposed). The confidence interval was not
reported by the authors. For the same data, Gottlieb and Carr (1981) now re-
report an odds ratio of 6.12 (95% CI 0.73-283.1). The methods used to cal-
culate the odds ratios were not reported by any of the authors; however, a
review of the data indicates that the method of Haldane (1955) (I.e., adding
one-half to each cell) was used to calculate the 4.46 estimate. -It was not
possible to determine which method was used to calculate the 6.12 estimate
(Gottlieb and Carr, 1981) except that it was not by the methods of Fleiss
(1981) (OR = 6.10) or Cornfield (1956) (OR - 6.17, 95% CI 0.73-63.9). However,
none of the calculated odds ratios was significant.
This study has the same limitations as those previously reported by Gott-
lieb and Pickle (1981). Thus, this study is inadequate to determine an associ-
ation between gasoline and bladder cancer.
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4.2.2.4 Najem et al. (1982)—A case-control study of bladder cancer in north-
ern New Jersey was conducted by Najem et al. (1982). The cases consisted of
75 white, living, biopsy-confirmed bladder cancer patients who were consecu-
tively admitted to the private practice clinics of four urologists and to two
community hospitals in northern New Jersey during 1978, Of the 75 cases, 65
were males and 10 were females; the mean age was 66.8 years. Controls were
x
obtained from the same clinic and hospital populations as the cases and matched
for age (+_ 5 years), place of birth (born in New Jersey; born out of state),
sex, race, and place of current residence (by census tracts). Potential con-
trols with a history of neoplasms or "tobacco-related heart disease" were
excluded from the study. Two controls were selected for each case; however,
since eight of the initially accepted controls did not meet all of the matching
criteria, eight cases had only one control each.
Data were obtained from the 75 cases and 142 controls on demographic and
socioeconomic history, lifetime occupational history, residency, personal and
family medical and surgical history, blood type, history of smoking, ingestion
of coffee, cola beverages, alcohol, saccharin, and hair dye use. Occupational
history was determined for the period beginning at age 16 and ending at the
diagnosis of bladder cancer for cases. One year of employment was required for
a study participant to be classified as being employed in a particular industry,
Questions about specific jobs and chemical exposure were also used.
The data were analyzed by calculating estimates of the relative risk (odds
ratios) for each risk factor of Interest. Ninety-five percent two-tailed con-
fidence intervals were calculated by the modified exact confidence intervals
procedure (Rothman, 1975). Post-stratification of the data into never smoked,
ex-smoker, and current smoker subgroups addressed the influence of cigarette
smoking as a confounder. The homogeneity of stratum-specific odds ratios was
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tested by the method proposed by Breslow and Day (1980). The Mantel-Haenszel
odds ratio was used as the summary measure of association.
Of the 75 cases, 22 (29%) worked in what was classified as the petroleum
(fuel) industry, compared to 19 (14%) of the 142 controls. The odds ratio was
2.5 (95% CI 1.2-5.4). Adjusting for the effect of smoking, the odds ratio was
2.4 (95% CI 1.2-4.7), showing that the association of bladder cancer with
employment in the petroleum (fuel) industry was not associated with the smoking
status of the cases. Among those who never smoked, the odds ratio was 5.6; the
confidence interval was not reported by the authors.
The major limitation of this work is the authors' partial selection of
the control population from a urology clinic. Patients from a urology clinic
may have conditions that have etiological features in common with bladder
cancer. Specifically, cystitis (Howe et al., 1980; Dunham et al, 1968; Wynder
et al., 1963), urinary stones (Wynder et al., 1963), and obstructive lesions
from prostatic disease (Dunham et al., 1968) have all been found to be bladder
cancer risk factors. If these conditions (i.e., cystitis, urinary stones, and
obstructive lesions from prostatic disease) are associated with exposure to gas-
oline, the selection of controls with these conditions may have resulted in an
underestimation of the relative risk.
Other limitations are a lack of information on gasoline exposure or job
titles, no analysis of latency or length of employment, a lack of detail on the
data collection procedures, and no adjustment for other high-risk occupations
identified by the authors as significant risk factors (work in the dye industry
and work in the plastics industry).
Thus, this study provides insufficient evidence for the carcinogenicity of
gasoline vapors.
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4.2.2.S, Mclaughli n et al.(1984)—A population-based case-control study of
renal cell carcinoma was conducted by Mclaughlin et al. (1984). This study was
also presented at a workshop on the renal effects of petroleum hydrocarbons
(Mclaughlin, 1984). Cases were white residents, ages 30 to 85, of the seven-
county Minneapolis-St. Paul, Minnesota, SMSA who were diagnosed with renal cell
carcinoma (ICD-8 189.0) from January 1, 1974, to June 30, 1979. Cases were
identified from records obtained from all hospitals in the SMSA and from the
Mayo Clinic 70 miles away. The authors believed that "complete case ascer-
tainment" was achieved, resulting in the identification of 506 cases (sex not
specified). Next-of-kin interviews were obtained for all cases that were
deceased (237) or too ill to be interviewed (14), Of the cases ascertained,
Interview data were obtained for 495 (98%) cases, 313 males and 182 females.
An age- and sex-stratified random sample of white controls, ages 30 to 64,
was selected from the telephone listings of the SMSA (additional details on
this sampling frame were not provided). An age- and sex- stratified systematic
sample of white controls, ages 65 to 85, was selected from Medicare listings
for the SMSA. A total of 714 population-based controls were identified from
these two sources; of these, interviews were obtained from 697 (98%).
To evaluate the possible bias of proxy interviews, a supplementary death
certificate control group was randomly selected from state mortality records
for the SMSA and frequency-matched to the cases on the basis of sex, age at
death, and year of death. Excluded as controls were those persons whose cause
of death was urinary tract cancer. Of the 495 supplementary controls identi-
fied, next-of-kin interviews were obtained for 493 (98%).
In-person interviews were conducted in the homes. For 14% of the subjects
who had moved out of the study area or who could not be interviewed at home,
interviews were conducted by telephone. Data were collected on demographic and
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ethnic variables; diet, beverage, and smoking history; drug use; and medical,
occupational, and residential history. "Exposures after 1973" were excluded
from the analysis. Details as to which exposures were excluded,, and why, were
not reported by the authors.
Odds ratios were calculated to estimate relative risk (Fleiss, 1981).
Confounding was controlled by calculating summary odds ratios by the maximum
likelihood method. Confidence intervals were calculated by a modification of
Cornfield's exact method (Gart, 1970). The logistic regression procedure was
used for further multivariate analysis (Breslow and Day, 1980). Dose-response
effects were tested with the Mantel extension test for linear trend. All odds
ratios were adjusted for age and calculated with data for all cases compared to
the population-based controls. To evaluate differences by respondent status
(i.e., personal or next-of-kin), odds ratios were also calculated adjusting for
respondent type by comparing directly interviewed cases to directly interviewed
population-based controls and comparing next-of-kin cases to next-of-kin inter-
viewed death certificate controls.
Renal cell carcinoma risks were assessed for 12 industries of usual employ-
ment and 28 industries or occupational activities "associated with high risk
for urinary tract cancer." None of these was found to be statistically sig-
nificant; however, risks for employment in the chemical and petroleum industry
were elevated (OR = 1.4) among males even after adjusting for age and cigarette
smoking. Risks were also elevated for males employed in the agricultural
industry (OR = 1.4) and the food products industry (OR =1.4).
Risks were also assessed for 25 occupational "materials previously linked
to urinary tract cancer." Of the 25, only one—petroleum, tar, and pitch
products—exhibited a significant (p = 0.046; Mclaughlin, 1984) excess in risk
among males even after adjusting for age and smoking (OR = 1.7, 95% CI 1.0-2.9).
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This risk appeared greater fop those exposed to petroleum products for 20 or
more years (OR = 2.6, 95% CI 1.2-5.7) than for those exposed for less than 20
years (OR » 1.1, 95% CI 0.05-2.5). (The p value for a test of linear trend
was not reported.) Risks were also elevated among females (OR = 4.6) but not
significantly. The authors report that adjusting for respondent status (i.e.,
personal or next-of-kin) made "no appreciable change" in these results.
Renal cell carcinoma risks were also assessed for several other risk
factors. Many exhibited significant excesses. A significant (p < 0.01) dose-
response trend was observed among both males and females for increasing levels
of cigarette smoking; risks were relative to those who never used tobacco
products on a "regular basis," and all odds ratios were adjusted for age. Each
of the three point estimates for females were also significant (light smoking,
OR « 1.8, 95% CI 1.0-3.9; moderate smoking, OR = 1.9, 95% CI 1.0-3.5; heavy
smoking, OR - 2.1, 95% CI 1.1-4.6). The point estimate for males in the heavy .
cigarette smoking category was also significant (OR = 2.3, 95% CI 1.4-3.8).
A significant (p < 0.01) dose-response trend for progressive weight gain,
as measured by quartiles of the Body Mass Index (BMI) (I.e., weight/height2),
was observed for females after adjusting for age and smoking (OR = 1.2, 95%
CI 0.6-2.0; OR » 1.7, 95% CI 0.9-2.9; OR = 2.3, 95% CI 1.3-4.1). Risks were
relative to those in the lowest quartile. This pattern was not observed in
males.
All remaining analyses were adjusted for age and smoking in males and for
age, smoking, and relative weight in females.
A statistically significant increase in risk was associated with increas-
ing duration of use of phenacetin-containing analgesics among females (p for
trend < 0.05). After adjusting for respondent status (i.e.s personal or next-
of-kin), the risk associated with long-term use was reduced to 0.8 in males and
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2.0 in females. A statistically significant positive trend remained among
females.
Among males, a significant risk was also associated with self-reported
urologic diseases diagnosed before 1970: kidney infection (OR = 2.8, 95% CI
1.3-5.7), bladder stone (OR = X, 95% CI 1.6-X), kidney stone (OR = 2.3, 95$ CI
1.1-4.5), and kidney cysts (OR « 9.2, 95% CI 1.8-62.0). Among females, a sig-
nificant odds ratio was observed for kidney infection (OR = 2.2, 95% CI 1.1-
4.4), and a borderline excess was observed for kidney cysts (OR = X, 95% CI
1.0-X, Fisher Exact Test). The authors stated that adjusting for respondent
status (i.e., personal or next-of-kin) tended to increase the risk estimate.
Self-reported cardiovascular diseases (i.e., high blood pressure and stroke)
were also found to be significant risk factors in males (OR = 1.9, 95% CI
1.3-2.8, and OR = 3.5, 95% CI 1.9-10.6, respectively). Statistically nonsig-
nificant excesses were observed among the females for high blood pressure
(OR = 1.5), stroke (OR = 2.8), and diabetes (OR = 1.8).
Risks were elevated in both sexes for German and Irish heritage (i ,e.s
both parents were of the same ethnic background relative to those born in the
United States and who were not of the same ethnic background). Odds ratios
among the German and Irish males were statistically significant (OR = 2.2, 95%
CI 1.1-4.2, and OR = 3.5, 95% CI 1.0-12.0, respectively). Odds ratios among
the German and Irish males were elevated (p > 0.05) (OR = 1.5 and.1.9, respec-
tively). Risks were also elevated among both sexes for both those with Scan-
dinavian (male OR = 1,3; female OR = 1.3) or Czechoslovak!an (male OR = 1.3;
female OR = 1.8) heritage, although none of these was significant. Adjusting
for respondent status (i.e., personal or next-of-kin) appeared not to change
the results.
Coffee and tea consumption appeared unrelated to risk in males. There was
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an excess risk for heavy tea consumption (OR = 3.4, 95% CI 1.48.9) in females,
and no risk was apparent for coffee consumption. The use of diet soda or
artificial sweeteners was associated with a statistically nonsignificant excess
risk in males (OR = 1.8); a dose-response trend was not observed. No excess
was seen among females. Risks for beer consumption were elevated in both
sexes, although no clear trend was ascertained. Wine and hard liquor appeared
not to be associated with an increased risk of renal cell carcinoma.
To assess a possible protective effect for renal cell carcinoma, nutrient
indices for intake of vitamin A, retinol, carotene, and vitamin C were devel-
oped. The authors reported that "there was no clear trend of decreasing risk
with increasing consumption except perhaps for carotene and vitamin C in men."
Additional details were not presented. Increasing broccoli consumption among
females was associated with a lessening in risk (p < 0.05). A positive dose-
response trend (p < 0.05) was observed for meat consumption in both sexes.
The authors used a logistic regression analysis to examine the effects of
exposure to petroleum, tar, and pitch while simultaneously controlling for the
effects of age, cigarette smoking, relative weight (as measured by the BMI),
phenacetin use, ethnicity, kidney infection, kidney stones, and coffee, tea,
beer, and meat consumption. Risks were similar to those of the stratified
analysis with a regression OR of 1.6 (95% CI 0.92.7) compared to the stratified
OR of 1.7 (95% CI 1.0-2.9) for males. The evaluation of risk among females was
statistically nonsignificant (OR = 4.6). Logistic regression results were also
similar to the stratified analysis; smoking, relative weight, kidney infection,1
and Scandinavian heritage were all found to be statistically significant after
simultaneously controlling for all the other confounders.
This is a well-conducted study. The case identification methods used
were good, and the response rate for both cases and controls was excellent.
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The major limitation of this study is the lack of any information on gasoline
exposure. Thus, this study provides insufficient data on the association of
renal cell carcinoma and gasoline; however., this study does provide evidence of
an association of renal cell carcinoma and exposure to petroleum, tar, or pitch
products among those exposed 20 or more years.
4.2.2.6. McLayghlln et al. (1983)—In conjunction with the authors1 case-
control study of renal cell carcinoma (Mclaughlin et al., 1984), a population-
based case-control study of renal pelvis cancer was conducted (Mclaughlin et
al., 1983). This study was also presented at the workshop on the effects of
petroleum hydrocarbons (Mclaughlin, 1984). The study area, period of study,
methods of data collection and analysis, and the control population were
exactly the same as previously reported in this review (Mclaughlin et al.,
1984).
Cases were white residents of the area who were diagnosed with renal
pelvis cancer (ICD-8 189.1). Of the 78 cases ascertained, interviews were
obtained for 74 (98%); 73 of these were histologically confirmed, and 70 were
transitional cell carcinomas. Fifty percent of the cases were deceased by the
time of interview. Next-of-kin respondents provided interview data for these
cases. The final study population consisted of 74 cases (50 males, 24 females)
and 697 controls (428 males, 269 females).
A significant (p < 0.001) dose-response was observed for increasing amounts
of cigarette smoking (measured as pack-years) in both sexes after adjusting for
age. Not only was the trend significant, but each of the point estimates was
significant among males (light smoking, OR » 5.5, 95% CI 1.425.5; moderate
smoking, OR = 9.6, 95% CI 2.5-43.4; heavy smoking, OR = 10.7, 95% CI 2.7-48.9)
and females (light smoking, OR = 4.9, 95% CI 1.2-20.2; moderate smoking, OR -
7.6, 95% CI 1.9-31.3; heavy smoking, OR » 11.1, 95% CI 1.868.7).
4-149
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Additional analyses adjusted for age and cigarette smoking. Renal pelvis
cancer risks were assessed for 13 Industries of usual employment; none revealed
a significant association. Risks were also assessed for 21 "potentially high-
risk materials suspected to be related to urinary tract cancer." The risk for
exposure to petroleum, tar, or pitch was elevated (OR = E.4), though not signi-
ficantly. Excess risks were significantly associated with exposure to coal or
natural gas (OR = 2.9, 95% CI 1.0-8.2) and mineral or cutting oils (OR - 2.8,
95% CI 1.1-7.0). Statistically nonsignificant elevations were observed for
herbicides (OR » 3.4), organic solvents (OR =2.4), paint thinners (OR = 1.6),
pesticides, rodenticides, or insecticides (OR = 3.0), rubber dust (OR =2.5),
soot (OR « 3.0), welding or soldering material (OR = 1.7), pigments (OR - 2.3),
and leather dust (OR = 6.9),
Persons who used drugs containing phenacetin or acetaminophen on a regular
basis for periods of 3 or more years were at increased risk (male OR - 3.9;
female OR » 3.7), but the excesses were not statistically significant. Females
who used estrogen-containing drugs were also at increased risk (OR = 2.7, p >
0.05).
Males who drank coffee were at an increased risk (defined as those who ever
drank coffee, OR - 1.6, p > 0.05); a dose-response pattern was not observed.
There was no apparent increased risk for coffee consumption for females. A
significant (p < 0.001) dose-response trend was observed for increasing con-
sumption of tea in females; risks for females who drank three or more cups
per day were very high (OR - 18.8, 95% CI 5.3-68.5) even after adjusting for
age and cigarette smoking. Tea consumption was not a risk factor in males.
Adjustment for respondent status (i.e., personal or next-of-kin) did "little"
to alter these results.
This is a well-conducted study on a cancer about which little was previ-
4-150
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ously known. As with many of the studies cited earlier, the major limitation
is a lack of exposure information on gasoline. Risks for the material expo-
sures were not assessed by duration of exposure or latency. This is unfortu-
nate because limiting analysis to those exposed to petroleum, tar, or pitch for
20 OP more years may have revealed a significant excess, a. pattern that was
observed 'for renal cell carcinoma (Mclaughlin et a!., 1984). In conclusion,
this study provides insufficient evidence of an association between renal
pelvis cancer risk and gasoline exposure.
4.2,2,7. Pancreatic Cancer Mortality Studies in Louisiana
4.2.2.7.1. Pickle and Gottlieb (1980). Death certificates of 876 persons (399
white males, 259 white females, 125 black males, and 93 black females) who died
of pancreatic cancer between 1960 and 1975 in 19 parishes of Louisiana were
matched to death certificates of persons dying of other causes. Each certifi-
cate was individually matched by sex, race, age (within 5 years), year of death
(within 1 year), and parish of usual residence. Information abstracted from
each death certificate included usual residence and usual occupation and indus-
try. Data handling methods were the same as those used for the Gottlieb and
Pickle (1981) study described above.
Crude odds ratios were calculated (Woolf, 1954; Haldane, 1955) by sex and
race for pancreatic cancer risk associated with 16 industrial categories, 6
occupation groups, and residential proximity to 5 industries, including food
processing, sawmills, chemical manufacturing, oil refining, and paper. Con-
fidence intervals were reported in the form exp [In e ± 2 std error (In 8)]
where 8 is the point estimate of relative risk (i.e., approximately 95% con-
fidence intervals). Positive associations were examined in more detail by
logistic regression techniques.
The odds ratio for white males was elevated in the oil refining industry
4-151
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(OR * 2.11, CI 0.86-5.20), but this was not significant. The odds ratios were
elevated for other industries of employment, including metal and transport
manufacturing (OR = 1.23, CI 0.34-4.40), paper manufacturing (OR = 1.77, CI
0.77-4.04), chemical manufacturing (OR = 1.16, CI 0.393.41), and the communi-
cations and utilities industries (OR = 1.58, CI 0.40-6.25).
When studied by usual occupation, elevated odds ratios were seen for white
female white-collar workers (OR = 1.37, CI 0.78-2.42), white and black males
who were classified as operatives (white OR = 1.17, CI 0.77-1.79; black OR =
1.26, CI 0.48-3.28), and white male farmers (OR = 1.16, CI 0.82-1.65). The
only significant odds ratios occurred for married white female white-collar
workers at 3.09 (CI 1.04-9.17). The numbers of cases and controls for each
*
group were not given.
Both white males and white females showed elevated risks for pancreatic
cancer associated with residence near oil refineries (male OR = 1.16; female OR
= 1.19). Confidence intervals were not reported. Elevated risks were also
seen for black males living near chemical manufacturers (OR = 1.20) and for
black females living near oil refineries (OR = 1.42) and paper manufacturers
(OR = 1.33). The authors did not give the statistical significance of these
findings. The association between pancreatic cancer and nearness of residence
to the paper, chemical, and oil industries was further examined by calculating
the distance to each plant within 3 miles of the individual's residence.
However, results were inconsistent, and confounding of duration at residence
made any association inconclusive.
There are limitations to this study. Occupations within oil refineries
that may be indicators of gasoline exposure were not presented. Death certi-
ficate data are for the most part only fragmentary, depicting residence and
occupational histories for only a portion of the individual's lifetime. Data
4-152
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were not available from this type of study on possible duration of exposure or
latency. Possible confounding effects of risk factors such as smoking and
alcohol consumption were not taken into consideration. Thus, this study is
inadequate to link gasoline exposure with pancreatic cancer.
4.2.2.7.2. Gott11eb and Carr (1981). Data from the previous Pickle and Gott-
lieb (1980) study on pancreatic cancer were reanalyzed; this new analysis is
reviewed here as Gottlieb and Carr (1981). Odds ratios and 95% confidence
intervals for white male oil refinery workers were recalculated. It was not
possible to determine the methods used. Risks for the oil refinery workers
were two times greater than those of workers not employed as oil refinery
workers (OR = 2.21, 95% CI 0.836,48). Fifteen of the cases and seven of the
controls were employed as oil refinery workers. For the same study data,
Pickle and Gottlieb (1980) originally reported an odds ratio of 2.11 (95% CI
0.86-5.20). However, neither estimate, 2.21 or 2.11, showed a significant
excess in pancreatic cancer risk.
This study has the same limitations as those previously reported for
Pickle and Gottlieb (1980). Thus, this study is inadequate to link gasoline
exposure with pancreatic cancer,
4.2.2.8. Migle(1977)--Wigle reported on a lung cancer case-control study and
a lung cancer ecological study conducted in the urban centers of the cities of
Sarnia and London in Canada during the period 1969-73. Only the case-control
study is reported here. Cases were all deceased males whose cause of death was
cancer of the trachea, bronchus, and lung (ICD-A 162). Controls were deaths
other than lung cancer and were randomly selected by computer from the same
mortality tapes and individually matched to the cases on the basis of sex,
city, 5-year age group, and 5-year calendar period.
The final study population consisted of 348 cases and an equal number of
4-153
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controls. The distribution of the control deaths by major cause was reported
l
to be not significantly different (p = 0.16) from what was expected based on
the age-, sex-, and cause-specific proportionate mortality frequencies for the
two cities combined for the period 1969-73 (tested with a chi-squared statistic
with 11 degrees of freedom; additional details were not reported).
Information on the study population was obtained from microfilmed death
certificate records and included information on dates and places of birth,
death, and residency; marital status; occupation, including kind of work done
during "most of working life" and kind of industry; immediate, antecedent, and
underlying causes of death; information from autopsy; and history of surgery.
The 1971 Census of Canada Occupation Classification Manual was used to code
occupations. The Standard Industrial Classification Manual of Canada was used
to code Industry of occupation. Residence was coded to census tracts. It was
not possible to determine if the matching criterion for "city" was place of
death, place of residence, or usual residence.
The "major lifetime" occupation was recorded on the death certificate for
approximately 85% of the cases and controls. Approximately 82% of the cases
and 85% of the controls had information on the death certificate to indicate
that the decedent was employed at least 10 years in the recorded occupation.
The author reported a high risk of lung cancer for males employed in motor
vehicle repair shops; five cases and no controls were so employed. No estimate
of relative risk of lung cancer from working in motor vehicle repair shops was
presented, but 1t can be calculated by Anscombe's (1956) method (I.e., adding
1/2 to each cell) as 11.16, relative to those not employed in vehicle repair
shops. Those employed in petroleum refining appeared not to exhibit an excess
risk of lung cancer (5 cases and 12 controls were exposed).
The overriding limitation of this study is the lack of statistical control
4-154
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for smoking. Without smoking history information on the study population, it
is virtually impossible to interpret the data from a lung cancer case-control
study. Other limitations include a lack of information on gasoline exposure,
no analysis for latency or length of employment, and no control for other
confounding factors, e.g., other high-risk occupations or industries. These
limitations make this study inadequate as a basis for determining the carcino-
genic! ty of gasoline.
4.2.2,9. Lung Cancer Mortali ty Studi es In Loui si ana
4.2.2.9.1. Gottlieb et al. (1979). Due to exceptionally high mortality from
lung cancer 1n southern Louisiana and correlation studies Unking lung cancer
to occupations found in southern Louisiana, Gottlieb et al. (1979) undertook a
case-control study to determine the influence of occupational, residential, and
ethnic factors associated with lung cancer. Nineteen Louisiana parishes were
selected either because they had elevated rates of lung cancer among white
males during 1950-69 and/or because petroleum, chemical, or paper manufacturing
were industries in the parish. Death certificates from 3,327 people who died
of lung cancer between 1960 and 1975 were obtained and matched to the death
certificates of persons who died of causes other than cancer for sex, race, age
within 5 years, year of death within 1 year, and parish of usual residence.
Information concerning name, birthplace, residence at time of death, employment
industry, usual occupation, marital status, and parent's names were abstracted
from each death certificate. Occupation and industry were coded using the 1970
U.S. Bureau of the Census Index of Occupations and Industries. Each person
was classified into 1 of 22 industrial categories and 1 of 9 occupational
categories. Place of usual residence was used to classify each person as to
proximity to seven industries. Likelihood of Acadian ancestry was also deter-
mined for each individual and coded as probable, possible, or unlikely.
4-155
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Odds ratios were calculated by the Woolf (1954) and Haldane (1955) methods
(I.e., adding 1/2 to each cell) for each sex and race category (male, female
and black, white) for each of the 22 Industrial codes, 9 occupational codes, 7
proximity to industry codes, and the 3 Acadian ancestry categories. Positive
associations were examined in more detail by logistic regression models.
Significantly (p < 0.05) high odds ratios were seen for the following
occupational categories: fishermen (OR = 1.81, 95% CI 1.22-2.69), transport
equipment manufacture (OR = 2.20, 95% CI 1.14-4.25), and transportation ser-
vices (OR » 1.27, 95% CI 1.02-1.58). Smaller increases were seen for oil
refining (OR = 1.32, 95% CI 0.93-1.87), auto repair businesses (OR = 1.33, 95%
CI 0,90-1.97), and metal and machinery manufacturing industries (OR ~ 1.27, 95%
CI 0.75-2.14). Significant (p < 0,05) odds ratios were also calculated for
older (age greater than 62) workers in fishing (OR = 1.7, 95% CI 1.02-2.86) and
oil production (OR = 1.6, 95% CI 1.03-2.61) and younger workers (age less than
63) in the fishing and transportation industries (OR =1.9, 95% CI 1.00-3.42,
and OR » 2.7, 95% CI 1.21-6.22, respectively). Younger workers in the auto
repair business showed a doubling of risk (OR = 2.0, 95%); this was considered
of borderline significance (95% CI ~ 0.96-4.24). Logistic regression showed a
threefold increase (OR, observed numbers, and CI not reported) in risk associ-
ated with oil exploration and drilling in workers over 62 years of age in
parishes with petroleum or paper industries. Confounding factors controlled
for with the use of the logistic model Included age, marital status, year of
death, birthplace, parish of residence, Acadian ancestry, three broad occupa-
tional categories (white- and blue-collar workers and others), and interactions
between these variables.
Odds ratios for usual occupation were significantly (p < 0.05) increased
for white male craftsmen (OR = 1.16, 95% CI 1.01-1.34), operators (OR = 1.27,
4-156
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95% CI 1.04-1.55), and white female clerical workers (OR « 3.31, 95% CI 1.11-
9.85). Elevated risks (p > 0.05) were estimated for all four sex-age groups
for persons living in close proximity to oil refineries; risk estimates ranged
from 1.16 (95% CI 0.97-1.38) for white males to 1.88 (95% CI 0.99-3.57) for
black males. This could not be explained by employment in the industry, al-
though risks were elevated for oil refinery workers, particularly in parishes
that had both petroleum and chemical industries. Among those with probable
Acadian ancestry who died at 63 years of age or older, lung cancer risks were
increased approximately 1.5-fold in males and twofold in females.
This case-control study showed a number of occupations and industries
linked to lung cancer risk. Risks for persons living close to oil refineries
were elevated for the four age-race groups, but these were not significant.
Although risks were considered of borderline significance for males, risks were
also considered borderline significant for young males employed in the auto
repair business. However, results from this study cannot be used to indicate
that gasoline is associated with lung cancer. Information presented on job
categories was too broad to indicate if a job would have potential for gaso-
line exposure, except perhaps among males employed in the auto repair business.
In addition, death certificate studies are inherently limited. Industry,
occupation, and residence data provide at best only a crude description with no
details on changes, duration, or latency for these variables. A study of lung
cancer that does not include the effects of cigarette smoking, which is not
available from death certificates, may grossly confound the results. This
study indicates that more detailed work is needed to link cancer with petroleum
and gasoline exposure.
4.2.2.9.2. Gottlieb (1980). This study investigated lung cancer and the
petroleum industry in Louisiana. The data collection methods and the study
4-157
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population were the same as that previously reported (Gottlieb et al., 1979)
except that this study reported on males only (2,161 white, 642 black). The
author failed to explain why this study population (Gottlieb, 1980) had one
less black male death than the population reported in the earlier study (Gott-
lieb et al., 1979). Relative risks were estimated along with 95% confidence
intervals by modification of Miettlnen methods (Rothman and Boice, 1976).
A total of 200 cases (181 white, 7 black, and 12 cases in which occupation
was not specified) were employed in the petroleum industry, 125 in mining and
75 1n refining. Of the controls, 170 (153 white, 5 black, and 12 controls in
which occupation was not reported) were employed in the petroleum industry, 112
in mining, and 58 in refining. The overall relative risk for lung cancer in
the petroleum industry was significant: 1.19 (95% CI 1.05-1,35). For the sub-
category of oil-field workers, welders, operators, boilermakers, and painters,
the estimate of relative risk was also significant (OR = 2.33, observed cases =
69, 95% CI 1.42-3.85). When dichotomized on age at 60 years, those classified
as oil-field workers, both the younger (OR » 1.36, 951 CI 0.24-22.48) and old-
er workers (OR = 1.86, 95% CI 0.91-3.8), showed Increases in relative risk.
However, these were not significant. The odds ratio for those classified as
skilled workers in pumping or refining was barely significant (p < 0.05) at
2.43 (95% CI 1.01-5.86).
The controls were generally younger than the cases, with 59% of the con-
trols under 34 compared to 35% of the cases. The authors stated that this
reflects premature death from causes other than lung cancer, such as accidents
in individuals who might have later become cases. This may underestimate the
risk for lung cancer in this study population.
This study has shown that certain occupations 1n the petroleum industry
such as welders, operators, boilermakers, painters, oil-field workers, and
4-158
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workers 1n pumping and refining may be at Increased risk of lung cancer.
However, this study Is limited by the same problems as those In the previously
reported study. There was no control for confounding factors such as smoking.
There are inherent problems In death-certificate studies. Information on
gasoline exposure could not be determined from the job title information pre-
sented on death certificates. Thus, this study is inadequate to link gasoline
exposure to lung cancer.
4.2.2.9.3, Gottlieb and Carr (1981). Gottlieb and Carr (1981) presented a
reanalysis of the principal investigator's original lung cancer data (Gottlieb
et al., 1979; Gottlieb, 1980).
Odds ratios and 95% confidence intervals were recalculated for males (both
races combined) whose usual occupation was in the oil refinery industry or the
petroleum Industry. The authors did not report the methods used to calculate
these odds ratios or confidence intervals.
A comparison of the authors' original findings (Gottlieb et al., 1979;
Gottlieb, 1980) and recalculated findings (Gottlieb and Carr, 1981) is shown
in Table 4-3. Initially, findings were not reported as significant for workers
in the oil refinery Industry; however, significant findings were later reported
after the data were recalculated (OR « 1.32, 95% CI 0.93-1.87 and OR = 1.31,
95% CI 1.04-1.65, respectively). The increase in risk appeared limited to
males older than 63 (OR * 1.90, 95% CI 1.13-3.19). The authors present no
rationale for these differences.
A serious limitation to Gottlieb and Carr's reanalysis is that it is not
possible to duplicate, with the available information, their calculations of
the 95% confidence intervals. Additional limitations to this study were previ-
ously presented under Gottlieb et al. (1979) and Gottlieb (1980). Thus, this
study is inadequate to link gasoline exposure to lung cancer.
4-159
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TABLE 4-3. COMPARISON OF GOTTLIEB'S ORIGINAL AND RECALCULATED ODDS RATIOS
AND CONFIDENCE INTERVALS FOR LUNG CANCER AMONG ALL MALES, BY AGE
Cases Controls
Oriolntlfindings8'**
OR (95$ CD
Recalculated findings0
OR {99% CD
Oil refining Industry
< Age 63
> Age 65
AH occupations fn petroleum
SkilUd pumping and
r*flnln§ occupations
< Age 60
> Age 60
Total
76
18
58
200
54
29
25
2,805
58
58
20
170
36
26
10
2,805
1.52
I.I
1.7
1.19
(0
(0
(0
(1
Not
1.52
2.43
(0
(1
.95
.71
.96
.05
- 1.87)*
- l.79)a
- 2.94)a
- l.55)b
reported
.92
.01
- I90)b
- 5.86)b
1
0
1
1
i
1
2
.31
.99
.90
.2
.5
.1
.5
(1.04
(0.79
(1.13
(1.04
(1.08
(0.82
(1.01
- 1
- 1
_ 3
- 1
- 2
- 1
- 6
.65)
.25)
.19)
.34)
.07)
.50)
.17)
•Got+lieb *t at. (1979); ORs and CIs were calculated by using Woolfs (1954) and Ha I dan.'s (1955)
Mthods.
bQottlUb (1980)! ORs and CIs wara calculated by using Rothman and Boica's (1976) modification of
Nlattinwn's mthods.
C6attl!at> and Carr (I960; methods usad to calculate ORs and CIs wara not raportad. Using the available
data, it Is not posslbla to datarmlna what methods wara usad by tha authors.
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4,2.2.10, Other Cancer Mortality Studies In Louisiana
4.2.2.10.1. Gottlieb and Carr (1981). In addition to the previously reviewed
bladder, pancreatic, and lung cancer data, Gottlieb and Carr (1981) reported on
a second case-control study designed to determine if drinking water sources
were associated with cancer.
The study area was parishes in southern Louisiana, many of which were in-
cluded in the bladder, pancreatic, and lung cancer studies; however, this study
area also included urban parishes to maintain a "balance" in availability of
subjects by water source. The data processing methods were the same as previ-
ously described (see Gottlieb and Pickle, 1981). Cases were identified during
the period 1960-75 and were decedents whose cause of death was brain (N = 497)
or kidney (N = 351) cancer. These were matched to non-cancer decedents (i.e.,
controls) on the basis of age at death (_+ 5 years), years of death (_+ 1 year),
race, and sex. Results were also presented for esophageal cancer and leukemia;
however, the sizes of these study populations were not reported.
For individuals with occupations in the petroleum or petrochemical indus-
try, risks were significantly elevated for kidney cancer (OR = 2.27, 95% CI
1.01-5.43) and for esophageal cancer (OR » 3.19, 95% CI 1.35-8.37, p < 0.005).
Leukemia risks were considered of borderline significance (95% CI 0.99-2.92,
chi-squared statistic p < 0.05) and were observed to be 70% greater than for
those not employed in these industries (1.70, observed cases = 41, observed
controls =24).
The risk of brain cancer for workers in the chemical industry was signifi-
cantly elevated (OR » 3.52, 95% CI 1.09-14.8). Kidney cancer risks were eleva-
ted (OR = 6.06), though not significantly (95% CI 0.73-279.6, p < 0.10).
This study has the same limitations as the authors' other Louisiana case-
control studies. Death certificate studies have inherent problems; data are
4-161
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not available on length of exposure or latency, and confounding variables such
as smoking cannot be controlled for. It was not possible to determine actual
gasoline exposure or determine if petrol sum-related exposures were for refining
or petrochemical occupations. Thus, this study is inadequate to link gasoline
exposure to cancer.
4.2.2.11. Brandt et al. (1978)—The authors reported on the occupational
exposure to petroleum products of 50 male subjects, ages 20 to 65, diagnosed
with acute non-lymphocytic leukemia (ANLL) at the University Hospital at Lund,
Sweden, during the period 1969 through May 1977. Their occupational exposure
to petroleum products was compared to the exposure of subjects in three clin-
ical groups (controls): (1) 100 consecutive male patients, ages 20 to 65,
treated for nonmalignant disorders from the outpatient department; (2) 100
consecutive male patients, ages 20 to 65, treated at the allergic diseases
outpatient department; and (3) 22 males, ages 20 to 62, with chronic myeloid
leukemia (CML) and 10 males ages 41 to 63, with chronic lymphocytic leukemia
(CLL) seen during the same period as the patients with ANLL,
The authors found that 36% (18 of 50) of the cases were occupationally
exposed to petroleum products, whereas only 10% (10 of 100) of each of the out-
patient control groups were similarly exposed. Typical petroleum-related
exposures reported were workers at filling stations, bus or truck drivers,
operators of excavating machines or power saws, and road haulers. The differ-
ence in exposure between the cases and controls was significant (p = 0.002,
Fisher Exact Test). The differences between the occupational exposures of the
cases and the CML controls (3 of 22 were exposed) or the CLL controls (0 of 9
were exposed) were also significant (p = 0.04 and p = 0.03, respectively).
The authors did not estimate the risk of the exposed group relative to the
nonexposed group in their study population; however„ using the authors' data,
4-162
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it can be estimated that the ANLL cases are five times more likely (crude OR =
5.06) to have worked in petroleum-related occupations than either of the out-
patient control groups and four times more likely (crude OR = 4.3) than the
CML controls.
This study provides insufficient data and insufficient analysis with which
to draw conclusions on the causal association of gasoline vapors and acute
non-lymphocytic leukemia. The authors :undertook this study after discovering
that several of the ANLL patients worked in petroleum occupations. Hence, to
be objective the investigators should have chosen a different time period from
which to select cases. In addition, the authors provided no details on the
control population. The category of petroleum-related occupations was very
broad and included exposures other than gasoline. Actual gasoline exposures
were not quantified. No latency analyses were conducted. There were no con-
trols for confounding factors such as age.
4.2.2.12. Plotnlkov(1978)—Plotnikov reported on the results from a retro-
spective epidemiologic study of leukemia and lymphogranulomatosis (LS). This
study was originally reported by the author in Russian (1978); reviewed here is
an English abstract of that paper (CANCERLINE, 1978).
Leukemia or LG was diagnosed in 1,165 patients (acute leukemia, 314;
chronic myeloid leukemia, 220; chronic lymphoid leukemia, 388; LG, 239) in
Kuibyshev Province, U.S.S.R., between 1965 and 1974. These patients answered
a detailed questionnaire concerning occupational exposures. A control popula-
tion was used for comparison purposes, but the only detail provided on control
selection was that controls were "healthy" individuals.
Petroleum industry employees and employees who had occupational exposure
to dyes or organic solvents were 1.3 times more likely to be cases rather than
controls. It was also reported that cases were exposed more frequently to
4-163
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ionizing radiation or ultrahigh-frequency electromagnetic fields than were
controls. Conclusions were that these exposures increased relative risk for
leukemia and LG; however, relative risk estimates were not reported in the
English abstract.
The lack of any methodologic detail or relative risk estimates precludes
consideration of these data. Thus, this study is considered an inadequate
basis upon which to determine the carcinogen!city of gasoline.
4.3. EPIDEMIOLOGIC STUDIES IN PROGRESS
4.3.1. Historical Prospective Mortality Study of EmployeesExposed to Down-
streamGasoline in the Petroleum Industry
The American Petroleum Institute (API) has undertaken a historical pro-
spective mortality study of marketing employees exposed to downstream gaso-
line in the petroleum industry. This work is being performed by Environmental
Health Associates, Inc. (EHA) (Wong and Morgan, 1984 Unpublished). Marketing
employees are those workers involved in the bulk distribution operations at
gasoline distribution centers, excluding service stations. These workers are
primarily exposed to downstream gasoline (or gasoline after processing of
petroleum) during the flow into tank trucks and from leaking fill lines and
gasoline spillage. This study will involve 50,000 workers with a minimum of 6
months1 employment. Identifying data and employment history will be retrieved
and coded, with vital status ascertainment conducted through the SSA using the
National Death Index as a supplemental means of follow-up. Cause-specific SMRs
will be calculated using the U.S. national age-, cause-, race-, and sex-speci-
fic mortality rates for 5-year time periods. The study is just under way, and
it is estimated that it will take approximately 4 years to complete.
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4.3.2. Case-Control Study of Kidney Cancerand Hydrocarbon Exposure Among
Petroleum Company Workers,
A case-control study has been undertaken by Epidemiology Resources, Inc.
(ERI), on behalf of the American Petroleum Institute (API). The study will.
evaluate the risk of kidney cancer in relation to occupational exposure to
hydrocarbons, with particular attention given to those found in unleaded gaso-
line. A feasibility study recently done by ERI identified two case-control
study populations judged to be feasible {ERI, 1985 Unpublished). One, a nes-
ted design, involves the utilization of existing cohorts of workers that had
already been assembled at 7 of the 11 petroleum companies that have agreed to
participate in the study. These companies already have the results of mortal-
ity follow-up, and some data have been reported {Theriault and Soulet, 1979;
Hanis et a!., 1982, 1985a, 1985b; Morgan and Wong, 1983 Unpublished; Wen eft
al.., 1984a; Morgan and Wong, 1984 Unpublished; Divine et al., 1985; Nelson,
1985 Unpublished). The second study involves the analysis of death certifi-
cates through company mortality records. All participating companies maintain
some sort of mortality registry, though extent of coverage varies from company
to company. The use of both case-control study populations will serve to com-
plement the limitations of each.
ERI will assess exposure to light hydrocarbons, such as those found in un-
leaded gasoline, by dividing the work category of "refinery work" into specific
subcategories that permit a more detailed analysis of exposure while adjusting
for the confounding effects of other petroleum products such as asbestos. To
accomplish this task, job titles from each of the participating companies will
be receded to a uniform coding scheme. All job titles and/or departments, by
company and plant for each study participant, would be so coded. The data col-
lections phase has recently begun. API expects the case-control work to take
4-165
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approximately 2 to 3 years to complete.
4.3.3. Registry of Mortality of.Refinery Workers
The American Petroleum Institute Is sponsoring a mortality study In
refinery workers; it will be conducted by Environmental Health Associates, Inc.
(EHA) (Wong et a!., 1985 Unpublished). The objective of the study is to
identify and monitor the mortality experience of refinery workers throughout
the petroleum industry. Data collection will involve gathering of identifying
Information and work history for all eligible workers in participating refine-
ries. The criteria for eligibility and the identity of the participating
refineries were not available. The vital status of active and terminated
employees and active annuitants will be ascertained through company identifi-
cation for active employees and annuitants with positive evidence of death,
and through the SSA and the National Death Index for terminated employees and
annuitants without positive evidence of death. Under this study, an attempt
may be made to consolidate Schottenfeld et al.'s (1981) previously collected
data (from API's MSKCC Health Registry of Refinery Workers) with this new data
(Weaver, 1986). The EHA mortality registry work is currently ongoing. Data
are expected to be collected for a 10-year period (Weaver, 1986).
4.3.4. TheAustralian Petroleum Industry Health Watch Surveillance Program
This prospective cohort study, known as Health Watch, is being conducted
by the Australian Institute of Petroleum Ltd. (AIP) in conjunction with the
University of Melbourne, Department of Community Medicine (UM/DCM) (AIP-UM/DCM,
1983; Christie et al., 1984). The feasibility study was begun in 1979; actual
data collection began In 1981 with a baseline cross-sectional survey of all
eligible employees.
The study population includes all payroll employees who have worked at an
Australian petroleum industry site having 10 or more employees, and who have
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completed at least 5 years of employment 1n the petroleum Industry. Transport
drivers and office workers are included if their place of employment is phys-
ically an offshore drilling platform or a production, processing, storage, or
manufacturing site. Excluded are all employees working in Head Offices. The
study population is not fixed in numbers, since each year people who complete 5
years of service are added to the study population.
The baseline survey, carried out in 1979-80, obtained information on
potential confounding variables. Data were collected on age, sex, previous
employment, smoking and drinking history, and self-reported past medical his-
tory. Information on job descriptions was obtained by personal interview; all
other data were obtained by self-administered questionnaire. Of the 12,500
eligible workers, 11,596 subjects (10,970 men, 626 women) completed the survey,
representing a response rate of 92%.
Ultimately, Health Watch aims to incorporate directly measured exposure
data into the system; however, this remains a long-term goal. Currently, pre-
cise job descriptions serve as indirect measures of exposure, and occupations
are classified according to the system developed by the American Petroleum
Institute (Tabershaw Occupational Medicine Associates, .1979). Employees in
the Australian petroleum industry, particularly in refineries, typically carry
out several tasks simultaneously. Therefore, workers are asked to apportion
the amount of working time spent on each job task. These are coded separately
for up to six tasks. If a person performs more than six tasks simultaneously,
that person is coded "multiprocess." At each refinery site, and at one in
every five job sites, a 10% sample of self-stated job descriptions are valid -
ated for accuracy.
Data are provided twice yearly by the oil companies on (1) the mortality
of active employees and employees receiving pension benefits, (2) changes in
4-167
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employee status (i.e., retired, terminated, or transferred), and (3) new
employees. Death certificates for deceased employees are obtained from the
states and coded to the ICD-9; a diagnosis of cancer is coded to the ICD-
Oncology. ICD coding is undertaken by the Australian Bureau of Statistics.
Follow-up status of the surviving study subjects is determined at the end of
each calendar year. Tracing of terminated employees is by certified mail,
and vital status is ascertained through the Government Statist of the State.
Cancer morbidity is self-reported by study participants and certified by
the diagnosing physician, who supplies copies of relevant histological reports.
Cancer morbidity information is also obtained from each State Cancer Registry.
Non-cancer morbidity Information is not obtained, since self-reported serious
illness data was found to be unreliable during the .feasibility stage of the
study.
By the end of 1984, the Health Watch study population consisted of 9,142
persons (8,736 men, 406 women), representing 20,715 person-years of observa-
tion (AIP-UM/DCM, 1985). Of these, 47, or 0.005%, were lost to follow-up.
Of the total study population of men, 27% were considered office workers; 251
worked in refining process; 20% in transport; 13% in maintenance; 5% in storage
and handling; 5% in manufacturing, marketing, and packaging; 3% in offshore
production; and 2% in chemical manufacturing. Approximately a third of the
men were younger than 40, a third were ages 40 to 49, and a third were 50 or
older (38%, 31%, and 31%, respectively).
Preliminary results are available on data collected as of December 31,
1984 (AIP-UM/DCM, 1985). Among the 9,142 subjects, 64 deaths (2 female) were
observed. SMRs were calculated using the 1982 sex-, age-, and cause-specific
Australian mortality experience as the standard. SMRs were not calculated if
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the observed numbers of deaths or the expected numbers of deaths were less than
five.
The SMR for all causes of death among male workers was a nonsignificant
61 (observed = 62, 95% C! 46-78). This deficit suggests the healthy worker
effect. To further analyze this possibility, SMRs were also calculated using
the mortality experience of a working population, i.e., Australian Government
employees (AGRBO), as the standard. The SMR for males age 64 or younger, when
compared to the ASRBO, was 104 (95% CI 79-134) for all causes of mortality.
Using the Australian mortality experience as the standard, the SMR among
men for all causes of death by major job category revealed deficits for all job
categories except storage and handling (SMR = 107, observed ~ 7, 95% CI 43-
221). Significant deficits were observed for workers in refining (SMR = 38,
observed = 9, 95% CI 17-71), transport (SMR * 50, observed = 9, 95% CI 23-94),
and office work (SMR = 60, observed = 19, 95% CI 36-93). Using the AGRBO as
the standard, nonsignificant excesses (p > 0,05) were observed for male work-
ers (age < 65) in storage and handling (SMR = 196, observed = 7); marketing,
manufacture, and packaging (SMR= 63, observed =5), and maintenance (SMR =
141," observed = 11). The SMR among the male office workers (age < 65) was
100 (observed = 18), while deficits (p > 0.05) were observed among workers in
refining occupations and transport occupations (SMR = 59, observed = 8, and
SMR = 86, observed— 9, respectively).
Relative risks were calculated for all causes of mortality among the men,
using the mortality experience of the petroleum industry office workers as the
comparison population. Risks were again elevated (p > 0.05) for male workers
in storage and handling (RR = 1.87); marketing, manufacture, and packaging (RR
= 1.58); and among maintenance workers (RR = 1.36). Deficits (p > 0.05) were
observed for workers in refining (RR = 0.64) and transport (RR = 0.82).
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SMRs among men for major causes of death were calculated using the 1982
Australian mortality experience as the standard. The SMR for all cancers was
79 (observed = 22, 95% CI 49-119). Deficits (p > 0.05) were observed for all
major causes of death, and for respiratory diseases the deficit was statisti-
cally significant (observed = 0, expected = 5.15, 95% CI 0-72). Mortality data
by specific cause of death among the A6RBO population are not available; there-
fore, SMRs could not be calculated using the A6RBO as the standard.
The standardized incidence ratio (SIR) for all cancers was calculated
using the Victorian Cancer Registry 1982 data as the standard. The SIR for
men for all malignant neoplasms was 73; this was not significant (95% CI 46-
109).
Relative risks were also calculated for all cancers by job category among
men, using office workers as the reference population. The relative risk among
maintenance workers was slightly elevated (RR = 1.13, 95% CI 0.34-3.75), and
deficits (p > 0.05) were observed among refining (RR = 0.78) and transport (RR
- 0.89) workers. Risks were not calculated for the remaining job categories
because the number of observed deaths was less than five.
Health Watch estimates that by the year 1990, 85,000 person-years of ob-
servation will have accumulated. Future activities include the 1986 re-survey
of petroleum industry employees. This re-survey will provide updated informa-
tion on the present study population and collect baseline information on new
employees. Also in preparation is a paper on the smoking behavior of the study
population (AIP-UM/DCM, 1985). This may provide some very useful information,
since smoking information on workers in the American petroleum industry is not
available. It is anticipated that Health Watch will continue to issue annual
reports on the study's progress.
At the present time, this study provides insufficient data on which to
4-170
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evaluate the association between gasoline and cancer risk. However, study
activities planned for the future include quantitative estimates of exposure.
In addition, future analyses will be able to control for some very important
confounding variables (e.g., smoking, alcohol). Thus, at some future time, the
Health Watch project may provide sufficient data with which to evaluate the
association between gasoline and cancer risk.
4.4. SUMMARY OF EPIDEMIOLOGIC STUDIES
Fifty-five studies were reviewed to determine if there is any epidemio-
logic evidence for an association between gasoline exposure and cancer risk.
Since unleaded gasoline was only introduced in the mid-1970s, even recent
epidemiologic studies are not likely to show an unleaded gasoline effect
because of the long latency period generally associated with cancer. There-
fore, this review was not limited to unleaded gasoline exposure but rather
addressed any potential gasoline exposure.
Of the 55 studies reviewed, 7 evaluated the association between employment
in the gasoline service industry and cancer risk, 25 assessed cancer risks in
petroleum refineries, 19 evaluated employment in the petroleum industry as a
risk factor, and 4 were epidemiologic studies currently in progress. The types
of study design used were varied; 26 were case-control (hospital and population-
based), 20 were cohort mortality, 1 was cohort morbidity, 5 were proportionate
mortality, and 3 were nested case-control studies. Table 4-4 summarizes these
studies, excluding the four studies that are currently in progress.
There is an unknown amount of overlap between study populations, especial-
ly among the refinery populations, since multiple studies were conducted at
single refinery locations at about the same time. Therefore, the results
reviewed here may not represent independent events. The known geographic over-
lap of study populations can be seen in Table 4-5. Locations for four nation-
4-171
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TABLE 4-4. SUHMRY OF EPIDEHIOUWIC STUDIES REVIEWED
Author
Study population/Comparison population Typ* of study
Occupational exposure
et al. (1985)
Silvemtnet al. (1983)
Ho»»sen et at. (1962;
1983a,b); MoMMsen and
Aagard (l98Ja,b; 1964);
MoMisen and Sell (1963)
Primary liver cancer cases/Patients Case-control
s*l*ct*d from hospital records
Lower urinary tract cancer cases/Sample Caso-conlrol
of area telephone users and Hedfcare
participants
Bladder cancer cases/Registrants from Case-control
the Denmark National Register
Gasoline service station employment
Gasoline service industry; garage workers and
gas station attendants; trucking transporter
of petroleum products
Work with oil or gasoline; work with petroleum
or asphalt
Ooniano et al. (1965)
Ronal cell carcinoma cases/Patients
selected from hospital admissions
records
Case-control
Gasoline service station employment
Lin and Kessler (1961)
Lin and Kessler (1979)
Mi I ham (1983)
Tabershaw-Coopar (1974
Unpublished,
1973 Unpublished)
Hants (1977)
Pancreatic cancer cases/Patients selected
fron hospital admissions records
Case-control
Testicular cancer cases/Patients selected Case-control
from hospital discharge records
Gasoline station owners and attendants;
gasoline and fuel truck drivers; fuel
oil dealers; auto mechanics and repairmen/
Washington State's mortality eKperience
Petroleuro refinery hourly workers at
17 U.S. refineries/U.S, mortality
experience
Male oxployeas of the Imperial Oil Co./
Canadian mortality experience; an internal
"non-SKposed" group; an internal "non-
refinery" group
PMR
Cohort mortality
Cohort mortality
Employment in gasoline service stations and
garages or the dry cleaning business
Employment in gasoline service stations;
employment In garages
Usual Iffatim occupation as gasoline station
owners or attendants; gasoline or fuel truck
drivers; fuel oil dealers; or auto mechanics
or repairmen
Employment in one of the refineries for at least
I year; "high, "aadium," or "low" hydrocarbon
exposure
Employment by the company for at least I year
if an active employee Mid 5 years if a ter-
minated employee; daily exposure to crude
petroleum, gas,or breakdown products; daily
refinery site exposure
(continued on the following page)
-------
TABLE 4-4. (continued)
Author
Study population/Comparison population
Type of study
Occupational exposure
is et al. (1979) Male employees of the Imperial Oil Co./
An internal "non-exposed" group; an
internal "non-refinery" group
Cohort mortality Employment by the company for at least I year if
an active employee and 5 years if a terminated
employee; daily contact with petroleum or its
products, moderately exposed to petroleum or its
products; employment daily on a refinery site
Theriault and Goulet
(1979)
Hale employees at a Canadian oil
rafinary plant/Quebec, Canada mortality
experience
Cohort mortality Employment at the refinery for 5 or more years
Thomas et al. (1980)
Decedent males who at their time of
death were active members of the Oil,
Chemical, and Atomic Workers Inter-
national Union (OCAW) in TX/U.S. and
Texas mortality experiences
PMR
Union membership and employment at a plant where
the major operation was petroleum refining or
production of petroleum products
GO
Reeve et al. (1982)
Decedent males who had been members of
OCAW Local 4-449 in Texas City, TX/U.S.
mortality experience
FUR
OCAW Local. 4-449 membership and employment at
one of two petroleum refineries in Texas
City, TX
Hants et al. (1982)
Regular plant employees who worked at
the Exxon Baton Rouge, LA refinery
and chemical plant/U.S. mortality
experience
Cohort mortality Employment at the refinery or chemical plant
for at least I month
Rushton and Alderson
(1963)
Men who had worked at three oil distri-
bution companies in Great Britain/
Combined mortality experience of England
and Wales
Cohort mortality Employment of at least I year at one of the oil
distribution centers
Morgan and Wong (1983
Unpublished)
Employees at two Chevron refineries/
U.S. mortality experience
Cohort mortality Employment of at least I year at one of the
refineries
Morgan and Wong (1984
Unpublished)
Employees at e Mobil Oil Co, refinery
in Beaumont, TX/U.S. mortality exper-
ience
Cohort mortality Employment of at least I year at the refinery
(continued on the following page)
-------
TABLE 4-4. (continued)
Autnor
Study population/Caspar!son population
Type of study
Occupational exposure
Thomas *t ol. (1964)
WOT et al. (1981, 1962,
1963, I984a>
f>. Rushton and Aldarson
1. (I98la)
Decedent cases who were active or re- Masted caso-
tirod members of OCAV and whose causa of control
death Mas brain tumors, stomach cancer, or
leukemia/Decedents selected from records
of active and retired OCAW mubers, ex-
cluding those whose cause of death was
the sam as Hid cases* cause
En^loyees at a Gulf Oil refinery/U.S.
mortality experience
Male workers at any one of eight petro-
leum refineries in Great Britain/Com-
bined mortality experience of England
and Wales for English and Welsh re-
fineries and the mortality experience
of Scotland for Scottish refineries
Cohort mortality
Cohort mortality
Union membership and eMpioynent at one of the
three Beaumont-Fort Arthur, TX area refineries.
Refinery exposures were categorized as crude oil,
lube oil, treating, coking, greise plant,
utilities, maintenance and labor, receipt and
movement, laboratory, motor transport, and other
work categories
Employment at the Port Arthur, TX site. The re-
finery was engaged in refining crude oil and
manufacturing fuels, oils, lubricants, and
petrochemicals such as benzene, cumeno,
ethylene, and cyctohexane
Employment of at least I year at one of the
refineries
Schottenfeld et al.
(1961)
Thomas et al.
-------
TABLE 4-4. (continued)
Author
Study population/Comparison population
Type of study
Occupational exposure
Hen «t al. (19846
Summary) Study 6
Kidney cancer cases at a Gulf Oil Co.
refinery in Port Arthur, TX/Non-eancer
decedents; nixed controls, i.e., no
exclusion for cancer or vital status
Nested case-
control
Employment at the Port Arthur, TX refinery
ui
Kaplan (1962 Unpub-
lished, 1985
Unpublished)
McGrw* et al, (1965)
Hanis et al.
-------
TABLE 4-4. (continued)
Author
Study population/Comparison population
Type of study
Occupational exposure
Helson (1965
Unpublished)
Col* et at. (1972)
How *t al. (1900)
Full-tiw* regular employews from 10
U.S. refineries of Amoco Oil Co./U.S.
mortality experience
Bladder cancer cases/An age- and sax-
stratified sample of the adult
population of the area
Bladder cancer cases/Maighborhood
controls
Cohort nortal ity
Case-control
Case-control
Employment at one of the refineries for at least
6 iKHiths; job type (administrative, etc.); con-
tact with light aromatic hydrocarbons; contact
with heavy oils; contact with refinery products;
the latter 3 exposures were categorfiod
as none, occasional, routine, or unknown.
Petroleum product occupations; petroleum
workers excluding machinists and mechanics
Employment in the petroleum industry
Gottlieb and Pickle
(1981)
CFt
Decedent bladder cancer cases/Decedents
from the saw parish of residence,
excluding those whose cause of death
was bladder cancer
Case-control Usual industry of employment In the oil refining
industry; living "near" olI refineries
Gottlieb and Carr (1981)
Najemet al. (1962)
Mclaughlin et al.
(1964)
Decedents whose cause of death was cancer 7 Case-control
of the lung, pancreas, bladder, brain, studies
kidney or esophagus, or leukemia/Decedents
from the same parish of residence as
the cases, excluding those whose cause
of death was the sans as the cases' cause
Bladder cancer cases/Selected from Case-control
the same urology clinic and hospital
population as the cases
(tonal cell carcinoma cases/An age- and Case-control
sex-stratified random sample selected
from area telephone listings
Usual industry of employment in the oil re-
fining industry; living "near* oil refineries;
work in oil production; employment in the
petroleum industry; workers in oil explor-
ation and drilling; oil-field workers, welders,
operators, boiler-makers, or painters in the
petroleum industry; ski I led workers involved
in petroleum pumping and refining; auto
repair business
Employment in the petroleum (fuel) industry
Petroleum, tar, or pitch products; amployMnt
in the chemical or petroleum industry
(continued on the following page)
-------
TABLE 4-4. (continued)
Author
Study population/Comparison population
Type of study
Occupational exposure
HcLaughlin et a),
(1983)
Pickle and Gottlieb
(I960)
Migle (1977)
Renal pelvis cancer cases/An age- and Case-control
sex-stratified random sample selected
from area telephone listings
Decedent pancreatic cancer cases/ Case-control
Decedents fro* the same parish of
residence, excluding those whose cause
of death was pancreatic cancer
Decadent lung cancer cases/Decedents Case-control
fro* the same city, excluding those whose
cause of death was lung cancer
Petroleum, tar, or pitch
Employment in the oil refining industry;
residence "near" oil refineries
Enploymeflt in the oil refining industry'! oil
production occupations; auto repair business;
employment in the oil exploration and drilling
industry; living in "close proximity" to oil
refineries
Gottlieb (I960)
Brandt et at. (1978)
Plotniko* (I978>
Decedent lung cancer cases/Decedents Case-control
from the save parish of residence,
excluding those whose cause of death Mas
lung cancer
Acute non-fyofihocytic leukemia cases/ Case-control
Outpatient department patients treated
for non-malignant disorders; outpatient
department patients treated for aIlergic
diseases; patients with chronic myeloid
Isukssia and chronic lynphocytic leukemia
Patients diagnosed with leukemia or Case-control
lymphogranuloraatosis/"Health" individuals
Employment in the petroleum industry; oil-field
workers, welders, operators, boileonaksrs, or
painters in the petroleum industry; aaploywunt
as a skilled worker in petroleum pumping or
refining
Petroleum products. Typical job titles were
workers at filling stations, bus or truck .'
drivers, operators of excavating machines or
powersaws, and road haulers
Employment in the petroleum industry
-------
TABLE 4-5. STUDY SITE LOCATIONS3 OF EPIDEMIOL06IC STUDIES REVIEWED
Study site location
Study author
CALIFORNIA
Chevron refinery in Richmond
Chevron refinery in El Segundo
FLORIDA
Miami
GEORGIA
Amoco Oil Co. refinery in Savannah
ILLINOIS
Shell Oil Co. refinery in Wood River
Amoco Oil Co. refinery in Wood River
INDIANA
Amoco Oil Co. refinery in Whiting
LOUISIANA
Exxon Co. refinery in Baton Rouge
18 parishes 1n southern Louisana
19 parishes throughout Louisiana
MARYLAND
Amoco Oil Co. refinery in Baltimore
MASSACHUSETTS
Eastern Massachusetts including Boston
MICHIGAN
Detroit metropolitan area
Morgan and Wong {1983 Unpublished)
Morgan and Wong (1983 Unpublished)
Lin and Kessler (1981)
Nelson (1985 Unpublished)
McGraw et al (1985).
Nelson (1985 Unpublished)
Nelson (1985 Unpublished)
Hanis et al. (1982)
Hanls et al. (1985a)
Hanis et al. (1985b)
Gottlieb and Carr (1981)
Gottlieb et al. (1979)
Gottlieb (1980)
Pickle and Gottlieb (1980)
Gottlieb and Pickle (1981)
Gottlieb and Carr (1981)
Nelson (1985 Unpublished)
Cole et al. (1972)
Lin and Kessler (1981)
Silverman et al. (1983)
(continued on the following page)
4-178
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TABLE 4-5. (continued)
Study site location
Study author
MINNESOTA
Minneapolis-St. Paul area
MISSOURI .
Amoco Oil Co. refinery in
Sugar Creek
NEW JERSEY
Exxon Corp. refinery in Bayway/
Bayonne
Northern New Jersey
New Jersey State
NEW YORK
Buffalo
New York City
NORTH DAKOTA
Amoco Oil Co. refinery in Mandan
TEXAS
Gulf Oil Corp. refinery in Port
Arthur
Mobil Oil Corp. refinery in Beaumont
Texaco, Inc. refinery in Beaumont
Lin and Kessler (1981)
McLaughlin et al. (1983)
McLaughlin et al. (1984)
Nelson (1985 Unpublished)
Hanis et al. (1985a)
Hanis et al. (1985b)
Najem et al. (1982)
Stemhagen et al. (1983)
Lin and Kessler (1981)
Domiano et al. (1985)
L1n and Kessler (1981)
Nelson (1985 Unpublished)
Thomas et al. (1980)b
Thomas et al. (1982)b
Thomas et al. (1984)b
Wen et al. (1981, 1982, 1983, 1984a)
Wen et al. (1984b Summary)
Thomas et al. (1980)b
Thomas et al. (1982a)b
Thomas et al. (1984)b
Morgan and Wong (1984 Unpublished)
Thomas et al. (1980)b
Thomas et al. (1982a)b
Thomas et al. (1984)b
Divine et al. (1985)
Barron and Divine (1985)
(continued on the following page)
4-179
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TABLE 4-5. (continued)
Study site location
Study author
TEXAS (continued)
Exxon Corp. refinery In Baytown
Amoco Oil Co. refinery In
Texas City
Marathon Oil Co. refinery in
Texas City
OCAW locations in Texas
UTAH
Amoco 011 Co. refinery in
Salt Lake City
VIRGINIA
Amoco Oil Co. refinery in Yorktown
WASHINGTON
Washington State
WYOMING
Amoco Oil Co. refinery in Casper
U.S. NATIONWIDE
17 Refineries
19 Companies involved in petroleum
refining and petrochemical
manufacture
All Gulf Oil Co. sites nationwide
All Texaco, Inc., refinery, petro-
chemical, and research facilities
Hanis et al. (1985a)
Hanis et al. (1985b)
Thomas et al. (1980)b
Reeve et al. (1982)&
Nelson (1985 Unpublished)
Thomas et al. (1980)b
Reeve et al. (1982)b
Thomas et al. (1980)
Wen et al. (1984b Summary)
Divine et al. (1985)
Barron and Divine (1985)
Nelson (1985 Unpublished)
Nelson (1985 Unpublished)
Mil ham (1983)
Nelson (1985 Unpublished)
Tabershaw-Cooper (1974 Unpublished,
1975 Unpublished)
Kaplan (1982 Unpublished,
1985 Unpublished)
Schottenfeld et al. (1981)
Wen et al. (1984b Summary)
Divine et al. (1985)
Barron and Divine (1985)
(continued on the following page)
4-180
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TABLE 4-5. (continued)
Study site location
Study author
CANADA
A Shell-Canada refinery0 In Quebec
Provinces of British Columbia,
Nova Scotia, and Newfoundland
Sarnia and London, Ontario
Imperial Oil Co. sites
OTHER FOREIGN SITES
8 Petroleum refineries 1n
Great Britain
3 Oil distribution companies at
airport and blending plants in
Great Britain
Rural area in Denmark
Lund, Sweden
Kuibyshev Province, U.S.S.R.
Theriault and Goulet (1979)
Howe et aU (1980)
Wigle (1977)
Hanis (1977)
Hanis et al. (1979)
Rushton and Alderson (1981a)
Rushton and Alderson (1983)
Mommsen et al. (1982, 1983a, b)
Mommsen and Aagaard (1983a, b; 1984);
Mommsen and Sell (1983)
Brandt et al. (1978)
Plotnikov (1978)
aLocation of the Lin and Kessler (1979) study was not reported.
^Identification of the refinery provided by the principal author as a personal
communication.
cCompany Identification of the refinery provided by Epidemiology Resources,
Inc. (1985).
4-181
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wide cohort mortality studies of refinery workers were not known. It is esti-
mated that the overlap between study populations may be even greater than that
which is already known.
Statistically significant cancer findings for the studies reviewed are
presented by exposure in the following sections. Some of these findings may
have been due to chance because of the large number of multiple comparisons
made in a majority of these studies.
It should be noted that positive studies* rather than negative studies,
were more likely to be identified during the literature search phase of this
review. Studies, especially those of the case-control design, that failed to
find an association, may not have been identified.
4.4,1. Summaryof Epidemiologic Studies of Workers in the Gasoline Service
Industry
A few studies have been conducted on workers in the gasoline service in-
dustry (defined here as gasoline service station owners and attendants, garage
workers, gasoline and fuel truck drivers, and those who reported working with
gasoline). Of the gasoline studies that were identified, six were case-control
studies. Specific cancer sites investigated were liver as a primary site
(Stemhagen et al., 1983), lower urinary tract (Silverman et al., 1983), bladder
(Mommsen et al., 1982; 1983a, b; Mommsen and Aagard, 1983a, b; 1984; Mommsen
and Sell, 1983); kidney (Domiano et al., 1985), pancreas (Lin and Kessler,
1981), and testis (Lin and Kessler, 1979). The seventh study, a proportionate
mortality study of gasoline service station owners and attendants, and gasoline
and fuel truck drivers, was conducted by Mil ham (1983) in Washington State. No
cohort mortality studies were identified on workers in the gasoline service
industry.
The majority of these studies assessed employment in the gasoline Indus-
4-182
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try as a surrogate to gasoline exposure. In addition, the analyses were not as
thorough as they could have been. For example, latency analyses were generally
not conducted, and adjusting for confounders was not always done.
The major limitation of these studies is the lack of information on gaso-
line vapor exposure; there are no quantitative estimates in any of the studies
reviewed. In addition, workers in gasoline service stations are potentially
exposed to other petroleum products—motor oils, diesel fuel oils, and sol-
vents—as well as to exhaust from automobile and truck engines. It was not
possible to assess the effects of gasoline exposure independently of these
other exposures.
Table 4-6 shows the site-specific statistically significant (p < 0.05)
results for the case-control studies. Stemhagen et al. (1983) found that
male primary liver cancer cases were more likely to work in gasoline service
stations than were their matched controls (OR = 2.88), that this difference was
significant (95% CI 1.20-6.88), and that limiting analyses to hepatocellular
carcinoma cases and their matched controls increased the risk to 4.20 (95% CI
1.55-11.35). This study provides some evidence of an association between work
in the gasoline service industry and cancer risk. However, there are other
methodological limitations in addition to the exposure limitations already
mentioned. No latency analysis was conducted, and no estimate was presented of
risk while simultaneously controlling for the effects of alcohol consumption (a
known risk factor).
Mommsen et al. (1982) and Mommsen and Aagard (1984) found that males who
reported working with gasoline or oil were at significant excess bladder cancer
risk (OR = 2.71, 95% CI 1.21-6.10) even after significant confounding factors
(i.e., cigarette smoking, nbcturia, prostatic surgery, cheroot smoker, and
lowest socioeconomic level) were controlled for (OR = 2.32). However, this
4-183
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TABLE 4-6. SUMMARY OF SITE-SPECIFIC
STATISTICALLY SIGNIFICANT CANCER FINDINGS
FROM CASE-CONTROL STUDIES THAT EVALUATED EMPLOYMENT IN THE
GASOLINE SERVICE INDUSTRY AS A RISK FACTORS
Type of
cancer
Author
Occupational exposure
Primary liver
Bladder
Pancreas
Testis
Stemhagen et al.. (1983)
Mommsen et al. (1982)
Mommsen and Aagaard (1984)
Lin and Kessler (1981)
Lin and Kessler (1979)
Gasoline service station
employment
Work with gasoline or oil
Any work in gasoline
service stations and
garages or the dry
cleaning business; 10+
years employment in similar
work
Work in gasoline service
stations; work in garages
aAll findings are positive (p < 0.05).
4-184
-------
study provides insufficient data with which to evaluate the carcinogenicity of
gasoline. The authors' data collection methods may have created a bias in the
response, since the interviewers were aware of the case or control status of
the subjects. Furthermore, cases were interviewed in person or in the hospi-
tal, while controls were interviewed in their homes by telephone. The exposure
category included.oil as well as gasoline. No latency analysis or analysis by
duration of exposure was conducted.
Lin and Kessler (1981) reported that male pancreatic cancer cases were
significantly more likely to have been employed In occupations involving close
exposure to gasoline (e.g., service stations and garages) or in the dry clean-
ing business than were the controls (OR = 2.79). This risk appeared to be
positively associated with increasing duration of exposure (3 to 5 years'
exposure, OR = 1.27; 6 to 10 years1 exposure, OR = 3.80; 10 or more years' ex-
posure, OR = 5.07). However, it was not possible to determine if the observed
increase in risk was due to employment in gasoline occupations, dry cleaning
occupations, or some combined exposure to both. In addition, the authors'
analysis failed to control for the effects of other confounding variables, such
as alcohol consumption. Thus, this study provides insufficient data upon which
to evaluate the association between gasoline and pancreatic cancer.
Lin and Kessler (1979) also reported that cases of testicular cancer were
significantly more likely to be gasoline station attendants and garage workers
than were the controls. Only an abstract of this work was published and no
estimates of risk were presented. The lack of any methodologic detail precludes
consideration of the data.
Table 4-7 presents statistically significant ("p < 0.05) findings by study
population for Milham's (1983) proportionate mortality study of white males in
Washington State. Gas station owners and attendants had a significantly great-
.4-185
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TABLE 4-7. SUMMARY OF SITE-SPECIFIC STATISTICALLY SICHXFICAHT CAHCER FIHDIBSS FROM MILHAMS'S 1983
WASHIMGIOH STATE PHS STUDY, BY STUDY POPULATIONS EXPOSED8
Fuel
Gas station oil/gas Fuel oil Auto
Type of cancer (ICD-7 code) owners/attendants truck drivers dealers/workers mechanics/repairmen
All cancer (140-205) +
Buccal cavity/pharynK (140-148) +•
Digestive organs/peritoneum (150-159)
Esophagus (150) +
Large intestine (153)
Respiratory system (160-165) +
Trachea/bronchus/lung (162) +
Genitourinary organs
I Prostate (177) +
U Bladder/urinary organs (181) ' +
-------
ec proportion of deaths due to cancer of the bladder and other urinary organs
than did Washington State decedents whose usual occupation was not gas station
owner or attendant. Among the same study population, a significant deficit was
observed for cancer of the digestive organs and peritoneum, and for cancer of
the large intestine. Among fuel oil and gas truck drivers, a significant ex-
cess was observed for all cancers. There were no site-specific cancer excesses
or deficits observed for this latter group.
Mil ham also evaluated the mortality experience of white males whose usual
occupation was fuel oil dealer and worker, and auto mechanic and repairman, who
were assumed to have petroleum products exposure and potential gasoline expo-
sure. Significant cancer excesses were observed among the fuel oil dealers for
cancers of the buccal cavity and pharynx, prostate, brain, and lymphatic and
hematopoietic tissues. Among the auto mechanics, a significant excess mortal-
ity was observed for esophageal and respiratory system cancers, including a
significant excess for primary cancers of the bronchus, trachea, and lung.
There are several problems associated with the validity of any PMR analy-
sis. First, a PMR analysis is generally used when the population at risk is
not known, PMRs use only the deaths from a given study, but not the entire
population from the study setting. Hence, this type of study cannot give any
idea of the population's risk of dying from any given cause.
Second, a PMR analysis assumes that overall mortality 1s equal in the two
populations being compared. If this is not true, and if the mortality rate for
the study group is lower than for the comparison group for all causes of death,
the PMR will inflate the estimate of cause-specific mortality.
Mil ham (1983) used as his comparison population the mortality experience
of Washington State. The general population of Washington State will include
sick and disabled nonworking individuals, and thus is likely to have a higher
4-187 .
-------
mortality rate from all causes of death than the gasoline station workers or
the gasoline truck drivers. Therefore, Mil ham's cause-specific proportionate
mortality rate" as an indicator of risk 1s inflated.
Third, PMRs for two or more causes of death are interdependent rather than
independent, since the sum of the observed numbers of deaths equals the sum of
the expected numbers. Hence a deficit in one cause-specific mortality will
force an excess in another cause-specific mortality. Fourth, a PMR analysis
assumes that the classification and reporting of deaths in the study population
and in the comparison population are complete and comparable. Fifth, this type
of analysis, in compiling causes of deaths, assumes that both populations are
comparable.
In addition, no attempt was made to control for confounding factors such
as smoking. No latency analysis or analysis by duration of exposure was con-
ducted. This study is considered inadequate for evaluating an association of
gasoline exposure and cancer risk.
4.4.2. Summary of Epidemiologic Studies of Workers In the Petroleum Ref_i_n_1ng
Industry
Twenty-five studies were reviewed that assessed the risk of cancer among
petroleum refinery workers. Four of these were proportionate mortality studies,
17 were cohort mortality studies, 1 was a cohort morbidity study, and ^ were
of the nested case-control design. These studies are summarized In Table 4-4.
Table 4-5 shows the known locations for each of the refineries.
The refinery studies provided no qualitative or quantitative estimates of
gasoline exposure, although some data on total hydrocarbon exposure are avail-
able (Wen et a!,, 1984b Summary).
Typical of modern refineries 1s the operation of the equipment from a
computerized remote panel, which reduces the potential of exposures to work-
4-188
-------
ers. However, the system is such that some airborne contamination by the
various hydrocarbon components, and presumably gasoline, will occur. The
"greatest risk" is faced by maintenance workers who may be exposed for "sus-
tained periods of time" (Clayton Environmental Consultants, Inc,, Undated).
Some exposure will also occur during gasoline quality control sampling and
testing procedures, especially by workers in gasoline treating and blending,
and during the bulk loading of the gasoline for distribution and marketing
(Clayton Environmental Consultants, Inc., Undated). The amount of exposure
in these processes will vary depending upon many factors, including a worker's
particular job and the extent of refinery automation.
Little is known about the historical exposure of refinery workers to gas-
oline. Technological developments of the automobile engine have historically
been coupled with changes in gasoline composition. For example, post-1940
gasoline had higher aromatic and isoparafflnic hydrocarbon content than ear-
lier gasoline, and unleaded gasoline has higher concentrations of isoparaffins
and aromatics than leaded gasoline (Domask, 1984).
These changes over time in the refinery processes, coupled with the pas-
sage and implementation of health and safety standards, make an assessment of
historical gasoline refinery exposure difficult. However, it has been estima-
ted that the potential for gasoline exposure prior to the late 1960s is greater
than the present-day potential for exposure (conversation between D.E.B. Potter,
Dynamac Corporation, and Robert Reisdorf, Dynamac Corporation, 1986).
For some of these studies, employee job titles or work categories provided
some information on potential for gasoline exposure; however, it is not known
how indicative of exposure a particular job title or work category is. In
addition, a majority of the refinery studies failed to report any information
on job titles or employee work categories.
4-189
-------
Refinery workers are exposed not only to gasoline but also to other petro-
leum and petrochemical products manufactured within the refinery. It was not
possible to assess the effect of gasoline exposure independently of these other
refinery exposures. Hence, any of the results reviewed here may be confounded
by these other chemical exposures.
Statistically significant site-specific cancer findings from the cohort,
nested case-control, and PMR studies are shown in Tables 4-89 4-9, and 4-10,
respectively. The results for all cancer sites combined are equivocal: three
studies found statistically significant (p < 0.05) excesses of mortality (Tables
4-8 and 4-10), four studies found statistically significant excesses among
subcohort populations and statistically significant deficits among the total
cohort (Table 4-8), and eight studies found statistically significant deficits
for all cancer mortality (Table 4-8). However, there are several possible ex-
planations for the deficits observed in all cancer mortality, the most obvious
being that the results are indicative of the healthy worker effect (McMichael,
1976). Some evidence of the effect is provided in these data. All of the
American studies that found statistically significant deficits in all cancer
mortality used the U.S. general population as the comparison population. How-
ever, when a working population (i.e., nonexposed petroleum industry workers)
was used as the comparison population, a statistically significant excess of
all cancer mortality was observed (Hanis, 1977; Hanis et al., 1979). A similar,
but nonsignificant, pattern was seen in the Australian petroleum industry data
(AIP-UM/DCM, 1985). Therefore, these data provide evidence to suggest that the
deficits observed for all.cancer sites combined are due to the healthy worker
effect, and that cancer risks from many of these refinery studies may be under-
estimated because the healthy worker effect was not controlled for.
4-190
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TABLE 4-8. SUMMARY OF SITE-SPECIFIC STATISTICALLY SIGHIFICANT* CANCER FINDINGS FROM COHORT MORTALITY
STUDIES THAT EVALUATED EMPLOYtCHT ID THE PETROLEUM REFINERY INDUSTRY AS A RISK FACTOR
of caacmr (iCO-8 Coda)
All cancer (140-209)
- «/- *
- */- --*/--
Buccal cavity/pharynx (MO-M9)
Digastiv* system (190-159)
Esophagus (ISO)
Esophagus/stomach (150-151)
Sfxwach (151)
Ofh*r digoslivo system (152-159)
Intestines/rectum (152-154)
Intestines (152-153))
Large intestine (155)
Large intestine/ rectum
(153-154)
Rectum (154)
-
<•
*/-
*•
«•
•«•
-
-
-
*
«•
'
4-
-
-
-
-
-
*/-
*/-
-
-
'
«•/-
-
_
-
+
-»•
(continued on the following page)
-------
MBIE 4-8. (««*Inu«d»
45.
I
Typ* of c*nc*r (ICO-8 Code)
Otter Oi9«stiv« (155-159)
Li v«r/gal (bladder (155-156)
Pancreas (157)
4-
•»•
-
_
-
-
-
R»s[>ir»tory systwi (160-163)
Nasal cavity/eifiusds (160)
Lun9/j»l«ura/oth»r rasp. (162-163)
Trachea/bronchus/ lung (162)
-
*/-
*
-
+
-
-
+/-
-
-
+
*
-
-
-
-
-
-
NesottwtioM
1
*
Bon* (170)
4-
Skin (172-173)
MfttanoBa (172)
--
+
*
+
(continued on the following page)
-------
TABLE 4-8. (continued)
4*
I
M3
CO
Typ* of cancer (ICO-8 Code)
Genitourinary organs (180-189) j
Prostet* (185) [
Urinary organs (188-169) I -
1
Bladder (188) 1
-
-b
-
-
-
Brain/other nervous system (191-192) I
«•
•
'
Ly»phatic/h«Mtopoi«tic tissues (200-209) 1
Lyvptto- and reticulosarcoma (200)
Lywphosarcooa (200,1)
Noo-Hodgkin's lywphoid (202) I
Multiple myeloM (20)) I
L.ukeni a/a leukemia (204-207)
Lymphatic leukemia (204)
Chronic lymphatic leukemia (204.1) I
Hyelofibrosis (209) 1
|
-
«•
*
1
+c
«.
+
*
•f
*
+
+
1
+
-
(continued on the following page)
-------
•£»
I
TABLE 4-8.
-------
TABLE 4-9. SUMMARY OF SITE-SPECIF 1C
STATISTICALLY SIGNIFICANT CANCER FINDINGS
FROM COHORT MORTALITY STUDIES THAT EVALUATED EMPLOYMENT IN THE
PETROLEUM REFINERY INDUSTRY AS A RISK FACTOR3
Type of cancer
Author (p values)
Occupational exposure
Stomach
Brain and benign
and unspecified
brain tumors
Thomas et al. (1984)
(p < 0.10)
Barron and Divine (1985)
(p < 0.05)
Employment in the unit
operations of maintenance
and labor; employment in
the yard subcategory of
maintenance; lube oil
workers
Employment in Texaco
research laboratories
aExcluded from this table are significant findings where the authors reported
that the measure of central tendency (i.e., mean, median) of the length of
employment was longer for the controls than for the cases.
4-195
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TABLE 4-10. SUMMARY OF SITE-SPECIFIC STAT1STICALLS SIGHIFXCAMT CAHCER FIMDIKGS FROM PMR STUDIES THAT EVALUATED
EMPLOYMENT IH THE PETROLEUM REFIHERY INDUSTRY AS A RISK FACTOR8
OCAW decedents from
OCAW decedents from three refineries in OCAU Decedents from a
refineries in Texas Beaumont-Port Arthur, TX refinery in Texas City, TX
Type of cancer (ICD-8 code) (Thomas et al,, 1980) (Thomas et al., 1982a> (Reeve et al., 1982)
All cancer (140-209) + +
Digestive organs/peritoneum (150-159) t
Stoaach (151) + +
Pancreas (157) + +•
Respiratory system (160-163) +
Lung/pleura/other respiratory (162-163) + +
Skin (172-173) + *
Genitourinary organs (180-189)
Prostate (185) +
Bladder (188)
Kidney (189) +
Brain/other nervous system (191-192) + +
Lymphatic/henatopoietic tissues (200-209) +
Hodgkin's disease (201) . +
Mon-Hodgkins lymphoma (202) +•
Multiple myeloma (203)
Leukemia (204-207) -i-
aSignificant (p < 0,05) excesses (+) or deficits (-) are reported.
-------
In addition,, most of the refinery cohorts were composed of all workers at
the refinery, including clerical and administrative personnel, refinery opera-
tors, technicians, and maintenance personnel. Thus, total cohort analyses will
dilute the estimate of risk for those most likely to be exposed (i.e., opera-
tors, etc.) and, in fact, an estimated 29% of the Wen et al. (1983, 1984b Sum-
mary) cohort (Moure-Eraso and Itaya, 1985) and 27% of the Australian cohort
(AIP-UM/DCM, 1985) consisted of management and clerical workers. Thus, cancer
risks among workers involved in the actual refinery processes are probably
underestimated in the refinery cohort data.
Finally, for safety reasons, smoking is prohibited in many parts of the
refinery (conversation between D.E.B. Potter, Oynamac Corporation, and Robert
Reisdorf, Dynamac Corporation, 1986). Thus, deficits in all cancer mortality
may be due to lower rates of mortality from smoklng-related cancers among
refinery workers 1n comparison to the general population.
These data suggest that cancer risks may be underestimated in these
studies. A review of the site-specific cancer results follows.
The results for digestive system cancer are ambiguous. This may be due
to the combined nature of the digestive system cancer category, which included
cancer sites for which excesses were observed (e.g., stomach cancer) as well as
sites for which deficits were observed (e.g., liver cancer). Four studies did
report statistically significant excesses of digestive system cancer mortality
among petroleum refinery workers (Tables 4-8 and 4-10). These excesses were
among selected subcohort populations: non-white males, those with routine expo-
sure to light aromatic hydrocarbons (I.e., benzene, toluene, and xylene), and
those with at least 30 years' employment in the refinery industry. Significant
excesses were also observed at refinery locations in Whiting, Indiana and Bay-
way /Bayonne, New Jersey. Significant deficits for digestive system cancer were
4-197
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observed among total cohort populations and selected subcohort populations
(Tables 4-8 and 4-10).
Cancers of the esophagus. Intestines, and rectum were detected In at least
one study (Table 4-8), and statistically significant excesses of stomach cancer
were observed by five teams of researchers among several refinery subcohort
populations (Tables 4-8, 4-9, and 4-10). These subcohorts included non-white
males; workers in specific refinery work categories—laborer, rigger, fire and
safety worker, lube oil worker, maintenance and labor employee, and yard main-
tenance worker; and workers at specific refinery locations in Whiting, Indiana
and in Great Britain (Table 4-9). One study, a nested case-control study of
stomach cancer (Thomas et a!,, 1984), reported a statistically nonsignificant
positive dose-response trend for duration of employment among refinery mainten-
ance workers, a work category considered to have potential gasoline exposure.
Significant deficits of stomach cancer were observed among salaried
employees, a group not likely to be exposed; among the total cohort at the El
Segundo refinery in California; and among refinery workers with 20 to 39 years
latency at a Beaumont, Texas refinery. However, the Beaumont refinery is
located in a county where the white male age-adjusted stomach cancer mortality
rate is significantly lower (p < 0.05) than the mortality rate of the U.S.
population (Mason et al., 1975). Thus, the deficit among males with 20 to 39
years1 latency may be due to the comparison population used. This study used
the U.S. general population, which has a higher stomach cancer mortality rate
than the county in which the plant is located. It is concluded that limited
evidence to suggest an association of stomach cancer risk and employment in the
petroleum refining industry.
As previously mentioned, for safety reasons tobacco smoking is generally
prohibited within a refinery setting, and this is reflected in the lung cancer
4-198
-------
mortality patterns of the refinery workers. Specifically, ten studies found
significant (p < 0.05) deficits of lung cancer mortality when refinery workers
were compared to the general population. This provides supporting evidence to
suggest that refinery workers, excluding office workers, smoke less—at least
at work (conversation between D.E.B. Potter, Dynamac Corporation, and Robert
Reisdorf, Dynamac Corporation, 1986)—than the general population.
Only three of the cohort mortality studies used a nonexposed petroleum
industry group as the comparison population. Each of these found excesses
of respiratory system cancer (Hanis, 1977; Hanis et al.s 1979; Hanis et al.,
1985b). Hanis (1977) and Hanis et al. (1979) found a statistically significant
(p < 0.05) excess of lung cancer among Imperial Oil Co. workers known to have
daily exposure to petroleum or its products, in comparison to the nonexposed
workers. Among Exxon refinery workers, Hanis et al. (1985b) found a 70% excess
(p < 0.05) of respiratory system cancer among potentially exposed refinery
workers when compared to the nonexposed workers after post-stratifying for
smoking. An excess of lung cancer was also observed by Morgan and Wong (1984
Unpublished) among non-white males with at least 40 years' latency. Thus,
some limited evidence exists to suggest an association between respiratory
system cancer risk and petroleum refinery industry employment.
Six studies found statistically significant (p < 0.05) excesses of skin
cancer mortality (ICD-8 172-173) among petroleum refinery workers (Tables 4-8
and 4-10). Three of these studies provide evidence that the skin cancer excess
was melanoma (ICD-8 172) (Rushton and Alderson, 1981a; Nelson, 1985 Unpublished;
Reeve et al., 1982). However, there is some overlap of study populations be-
tween the Reeve et al. (1982) and the Nelson (1985 Unpublished) studies (Table
4-5); at least three of the deaths reported by Reeve et al. were also included
in the Nelson cohort.
4-199
-------
Three cohort mortality studies and one cohort morbidity study found sta-
tistically significant (p < 0.05) excesses of leukemia among refinery workers
(Table 4-8). (The term leukemia is used here to mean all of the leukemias,
ICD-8 204-207.) A fifth study, a nested case-control study by Thomas et al.
(1984), found a statistically nonsignificant positive dose-response relation-
ship between duration of employment and leukemia mortality among refinery
workers involved with treating processes, a work category with potential gas-
oline exposure.
Excess of leukemia mortality and morbidity may be associated with the
presence of benzene in gasoline or in the petroleum refinery. Epidemiologic
studies have suggested significant increases in leukemia among workers with
probable past exposure to benzene (Rinsky et al., 1985), and the CA6/EPA con-
siders the evidence for cardnogenicity to humans to be sufficient (Linet,
1986). Morgan and Wong (1983 Unpublished) found evidence to suggest that the
leukemia excess observed among the Chevron cohort was associated with a his-
tory of refinery employment prior to 1949, when the recommended benzene stan-
dard was lowered to 35 ppm from 100 ppnu
The literature does suggest that benzene-induced leukemia tends to be
myelocytic (Heath, 1982); however, two of the refinery studies found signif-
icant excesses of lymphatic leukemia (Table 4-8), a leukemia not associated
with benzene exposure. Additionally, some evidence suggests the possibility
that organic solvents other than benzene may play a role in the development of
leukemia (McMichael et al., 1975). Significant excesses were also observed
among the other lymphatic and hematopoietic tissues, specifically lymphosar-
coma, non-Hodgkin's lymphoma, multiple myeloma, and myelofibrosis (Table 4-8).
Thus, these refinery studies provide limited evidence to suggest an associa-
tion between lymphatic and hematopoietic tissue cancer risk and employment in
4-200
-------
the petroleum refinery industry.
There were no cohort mortality studies of refinery workers that found
statistically significant excesses of bladder cancer; statistically significant
deficits of bladder cancer were observed by five research study teams. This is
in contrast to three case-control studies that found that males who reported
working with gasoline or oil or in the petroleum industry were at significant
excess bladder cancer risk (Tables 4-6 and 4-11). This inconsistency may be
explained by the fact that the 5-year survival for white male bladder cancer
cases is high (54%) in comparison to the survival of white males diagnosed with
stomach cancer (12%)t lung cancer (9%), or acute leukemias (15%) (Silverberg,
1984), Thus, cohort mortality studies that evaluate the risk of bladder cancer
do not represent the true incidence of bladder cancer in the population, and
bladder cancer risk may be more truly reflected in case-control studies.
Four studies found statistically significant mortality deficits among re-
finery workers whose cause of death was cancer of the liver, gall bladder, or
other biliary passages (ICD-8 155-156). No significant excesses were observed.
These data are difficult to interpret because of the combined nature of the
category and because alcohol consumption is a strong confounding factor that
was not controlled for. However, evidence of an association between liver
cancer and refinery employment was not observed in these data.
There are serious limitations to all of these refinery study findings, one
of the most important being that the majority of the studies did not conduct
analyses of latency, nor did they evaluate possible dose-response effects or
analyze for duration of employment. Failure to examine cancer risks within the
context of time or dose lessens the chance that an excess cancer risk will be
identified. Rather, a dilution of risk is likely to occur in the absence of
these analyses.
4-201
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TABLE 4-11. SUMMARY OF SITE-SPECIFIC STATISTICALLY SIGNIFICANT CANCER
FINDINGS FROM CASE-CONTROL STUDIES THAT EVALUATED EMPLOYMENT IN THE
PETROLEUM INDUSTRY AS A RISK FACTQRa
Type of cancer
exposure
Author
Occupational
exposure
Esophagus
Lung
Lung
Bladder
Bladder
Kidney
Renal cell
Leukemia
Gottlieb and Carr (1981)
Gottlieb et al. (1979)
Gottlieb (1980)
Howe et al. (1980)
Najem et al. (1982)
Gottlieb and Carr (1981)
McLaughlin et al. (1984)
Gottlieb and Carr (1981)
Acute non- Brandt et al. (1978)
lymphocytic
leukemia
Leukemia/ Plotnlkov (1978)
lymphogran-
ulomatosis
Occupations in the petroleum or
petrochemical industry
Employment in the oil production
industry among those older than
62 years
Employment in the petroleum in-
dustry; petroleum Industry oil-
field workers, welders, opera-
tors, boilermakers, or painters;
skilled workers involved in
petroleum pumping and refining
Employment 1n the petroleum
industry
Employment in the petroleum
(fuel) industry
Occupations in the petroleum or
petrochemical industry
20+ years' exposure to petroleum,
tar, or pitch
Occupations in the petroleum or
petrochemical industry
Petroleum products. Typical
job titles were workers at filling
stations, bus or truck drivers,
operators of excavating machines
or powersaws, and road haulers
Employment in the petroleum
industry
aAll findings are positive (p < 0.05)
4-202
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The lack of statistical control for confounding factors such as smoking,
alcohol consumption, or diet is a major limitation in all of these studies.
This is especially important when interpreting bladder, liver, or lung cancer
findings. However, since smoking is generally prohibited within a refinery,
confounding due to cigarette smoking may actually have resulted in an under-
estimation, rather than an overestimation, of occupationally-related cancer
risk in comparison to the general population.
''• Many of the cohort studies had other limitations. The inclusion in the
cohort of employees not likely to be exposed was commonplace for most of the
refinery studies. The length of cohort follow-up was short for some of the
studies. Some of the methods employed for vital status ascertainment (e.g.,
searching only company records) may have resulted in an underreporting of mor-
tality for some of the study populations. All of these limitations can result
in underestimation of cancer risk.
In addition, the number of parsons lost to follow-up was sufficiently
large, for some of the studies, to call into question the author's findings.
Other limitations included a lack of detail on cohort tracing procedures and
cause-of-death coding procedures employed by some of the researchers (e.g.,
version of the ICD used, and whether coding was done by a trained nosologist).
At least two of the cohort studies did not use time-specific mortality rates to
calculate SMRs, thus, possibly biasing the risk estimates.
For two of the cohort studies, information on race was not available for
the entire cohort. Those individuals for whom race was unknown were assumed to
be white (this accounted for 2Q% of the cohort 1n one of these studies). This
assumption may have led to a biased estimate of risk.
Savitz and Moure (1984) have suggested that ethnicity is especially per-
tinent to an analysis of refinery data because of Texas' large Hispanic popula-
4-203
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tion. Lung cancer incidence rates among white male Hispanics were 34% of those
of "Anglo" males. The incidence of melanoma among Hispanics was 14% of that
among "Anglos" (Key, 1981). Thus, ethnicity may be an important confounder in
the data that could not be controlled for.
There are methodological limitations as well. Those associated with a PMR
analyses were discussed previously in detail (see section 4.4.1.). Most of
these same limitations apply to the PMR studies of refinery workers. Other
limitations include those associated with the healthy worker effect, also dis-
cussed previously.
Finally, the cohort mortality studies are limited by the inconsistency of
their results (see Tables 4-8, 4-9, and 4-10), some of which may be explained
by geographic variations or changes in cancer mortality patterns over time.
Some may also be due to differences in refinery practices or exposure defini-
tions. For example, many of the statistically significant deficits were ob-
served among the total cohort, while significant excesses were observed among
subcohorts of workers known to be exposed.
In spite of these limitations, there is evidence to suggest a possible
association between employment in the petroleum refining industry and risk
of stomach cancer, respiratory system cancer (i.e., lung, pleura, nasal cavity
and sinuses), and cancer of the lymphatic and hematopoietic tissues.
4.4,3. Summary of Case-Control Studies That Evaluated Employment in the
Petroleum Industry as a Risk Factor
Nineteen case-control studies were reviewed that evaluated employment in
the petroleum industry as a risk factor (Tables 4-4 and 4-5). These studies,
like the gasoline and refinery studies, are limited by their lack of gasoline
exposure Information. No quantitative estimates of exposure were available,
and 1t was not possible to determine 1f these workers were actually exposed to
4-204
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gasoline, although that potential existed. As 1n the gasoline and refinery
studies, the results reviewed here may be confounded by the other chemical
exposures associated with employment in the petroleum industry. Table 4-11
presents a summary of the site-specific statistically significant (p < 0.05)
cancer findings for these studies.
Of the 19 case-control studies that were reviewed, 2 provided limited
evidence of an association between cancer and employment in the petroleum in-
dustry. This evidence was provided by Mclaughlin et al. (1984) for renal cell
carcinoma and by Howe et al. (1980) for bladder cancer. Both studies were
population-based.
Mclaughlin et al. (1984) found that renal cell carcinoma cases were more
likely than controls to be exposed to petroleum, tar, or pitch products (p =
0.046). This risk remained even after adjusting for the confounding effects
of age and smoking (OR = 1.7, 95% CI 1.0-2.9), and this excess risk appeared to
be positively associated with length of exposure (< 20 years, OR = 1.1, 95% CI
0.05-2,5; 20 or more years OR = 2.69 95% CI 1.2-5.7). A logistic regression
analysis was also used to examine the effects of exposure while simultaneously
controlling for the effects of all significant confounding variables (age,
cigarette smoking, relative weight, phenacetin use, ethnicity, a history of
kidney infections or kidney stones, and consumption of coffee, tea, beer, and
meat). The logistic regression odds ratio of 1.6 was similar to that of the
stratified analysis (age and smoking adjusted OR = 1.7), although the logistic
estimate was not statistically significant (95% CI 0.9-2.7). This result was
to be expected, considering the small number of exposed persons.
Howe et al. (1980) found that bladder cancer cases were more likely to be
employed in the petroleum industry than controls (RR = 5.3, 95% CI 1.5-28.6)
and that this estimate remained unchanged after controlling for the eonfound-
4-205
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ing effects of smoking. (The authors' matched analyses also controlled for the
effects of age.) The findings of this study are considered limited because of
lack of latency and duration-of-employment analyses.
Each of the remaining 17 case-control studies that evaluated employment in
the petroleum industry as a risk factor provided insufficient data with which
to draw conclusions on the association between cancer risk and petroleum in-
dustry employment.
4.4.4. Summary of Epidemiol ogi cStudies in Progress
The American Petroleum Institute has recently begun three epidemiologic
studies that are directly relevant to this review: (1) a historical prospec-
tive mortality study of employees exposed to downstream gasoline in the petro-
leum industry, (2) a case-control study of kidney cancer and hydrocarbon expo-
sure among petroleum company workers, and (3) a prospective study of mortality
of refinery workers. Findings from the downstream gasoline study will be avail-
able in 4 years, and the results of the case-control study in 2 to 3 years. It
will be at least 5 years before the prospective study will have sufficient
power to detect an approximate doubling of risk for kidney cancer or stomach
cancer.
These studies also may have methodological limitations. Smoking histories
will not be available for cohort members in the downstream gasoline mortality
study. As was noted by the authors of the API feasibility study, "With no data
on smoking it ... (will) be difficult to determine whether any observed
mortality excess from tobacco-related diseases was due to employment, smoking,
or an interaction between both." (Wong and Morgan, 1984 Unpublished). In addi-
tion, it appears that an internal nonexposed group cannot be used as the com-
parison population (Wong and Morgan, 1984 Unpublished). Thus, these data may
be biased by the healthy worker effect as well as by smoking.
4-206
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The case-control study only Identifies cases of kidney cancer that re-
sulted in a mortality; it does not identify incidence cases. As noted by the
authors of this feasibility study, "mortality data might reveal as little as
50% of the number of incident cases in some age groups." {ERI, 1985 Unpub-
lished). Thus, a bias from incomplete ascertainment of the cases might exist
in this study. Data on the smoking habits of individual study participants
will not be available (ERI, 1985 Unpublished), and some studies have found a
dose-response relationship between smoking and kidney cancer (U.S. Public
Health Service, 1982; Mclaughlin et al., 1984). Therefore, these data may be
affected by the confounding effects of smoking.
A prospective cohort study 1s being conducted by the Australian Institute
of Petroleum Ltd. in conjunction with the University of Melbourne, Department
of Community Medicine (AIP-UM/DCM, 1983; AIP-UM/DCM, 1985; Christie et al.,
1984). This well-designed study will, at some future times permit the calcula-
tion of risk estimates while simultaneously controlling for important confound-
ing variables (e.g., smoking and alcohol). Quantitative estimates of exposure
will also be available. However, these results are several years away.
Three other refinery studies are known to be in progress or very recently
completed: a Shell Oil Co. study of the company's Deer Park refinery; a Mobil
Oil Paulsboro refinery study, with follow-up from 1946-79; and a Mobil Torrence
refinery study, with follow-up from 1959-80 (ERI, 1985 Unpublished). Addi-
tional details on these studies are not available as of this writing.
4.4.5. Conclusions
Fifty-five studies were reviewed to determine if there is any epidemio-
logic evidence for an association between gasoline exposure and cancer risk.
Since unleaded gasoline was only introduced in the mid-1970s, even recent
epidemiologic studies are not likely to show an unleaded gasoline effect be-
4-207
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cause of the long latency period generally associated with cancer. Therefore,
this review was not limited to unleaded gasoline exposure, but addressed any
potential gasoline exposure.
None of the studies reviewed provided qualitative as well as quantitative
estimates of gasoline exposure.
Seven studies were identified that evaluated the association between em-
ployment in the gasoline service industry and cancer risks; the industry here
Includes gasoline service station owners and attendants, garage workers, gaso-
line and fuel truck drivers, and those who reported working with gasoline. The
study by Stemhagen et al. (1983) provided some evidence of an association be-
tween gasoline service station employment and risk of primary liver cancer.
The remaining six studies were judged inadequate.
Twenty-five studies were reviewed that evaluated the association between
employment in a petroleum refinery (a work environment with potential gasoline
exposure) and cancer risk. Judged individually, these studies provided inade-
quate evidence of an association. However, judged collectively (Tables 4-8,
4-9, and 4-10) these studies provide suggestive evidence of an association
between employment in a petroleum refinery and risk of stomach cancer, respira-
tory system cancer (i.e., lung, pleura, nasal cavity and sinuses), and cancer
of the lymphatic and hematopoietic tissues.
Nineteen case-control studies were reviewed which evaluated employment
in the petroleum industry as a cancer risk factor. The study by Howe et al.
(1980) provided limited evidence of an association between petroleum industry
employment and risk of bladder cancer.
Also reviewed were four protocols of epidemiologic studies in progress.
These studies may provide evidence of an association between gasoline exposure
and cancer risk; however, these findings are 3 to 5 years in the future.
4-208
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In conclusion, these ep1dem1olog1c studies collectively provide limited
evidence that employment 1n the petroleum industry 1s associated with certain
types of cancer. However, the epidemiologic evidence for evaluating gasoline
as a potential carcinogen is considered inadequate.
4-209
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-------
5. QUANTITATIVE RISK ESTIMATION
This quantitative chapter deals with the estimation of cancer risk due
to exposure to unleaded gasoline vapor. The unit risk is defined here as the
lifetime incremental cancer risk from exposure to 1 ppm of gasoline vapor in
air. Uncertainties about the risk estimate and the possible role of benzene
content in gasoline vapor are also addressed in this chapter.
The risk estimate for gasoline vapor represents an extrapolation below the
dose range of experimental data. There is currently no solid scientific basis
for any mathematical extrapolation model that relates exposure to cancer risk
at the extremely low concentrations, including the unit concentration given
above, that must be dealt with in evaluating environmental hazards. For prac-
tical reasons the correspondingly low levels of risk cannot be measured direct-
ly either by animal experiments or by epidemiologic studies. Low-dose extrapo-
lation must, therefore, be based on current understanding of the mechanisms of
carcinogenesis. At the present time the dominant view of the carcinogenic pro-
cess involves the concept that most cancer-causing agents also cause irrever-
sible damage to DNA. This position is based in part on the fact that a very
large proportion of agents that cause cancer are also mutagenlc. There is ,
reason to expect that the quanta! response that is characteristic of mutagen-
esis is associated with a linear nonthreshold dose-response relationship. In-
deed, there is substantial evidence from mutagenicity studies with both ionizing
radiation and a wide variety of chemicals that this type of dose-response^model
is the appropriate one to use. This is particularly true at the lower end of
the dose-response curve; at high doses, there can be an upward curvature, prob-
bably reflecting the effects of multistage processes on the mutagenic response.
The linear nonthreshold dose-response relationship is also consistent with the
5-1
-------
relatively few epidemiologic studies of cancer responses to specific agents
that contain enough information to make the evaluation possible (e.g., radia-
tion-induced leukemia, breast and thyroid cancer, skin cancer induced by
arsenic in drinking water, liver cancer induced by aflatoxins in the diet).
Some supporting evidence also exists from animal experiments (e.g., the initi-
ation stage of the two-stage carcinogenesis model in rat liver and mouse skin).
Because its scientific basis, although limited, is the best of any of the
current mathematical extrapolation models, the nonthreshold model, which is
linear at low doses, has been adopted by the Carcinogen Assessment Group (CAG)
as the primary basis for risk extrapolation to low levels of the dose-response
relationship. The risk estimates made with such a model should be regarded as
conservative, representing the most plausible upper limit for the risk (i.e.,
the true risk is not likely to be higher than the estimate, but it could be
lower).
For several reasons, the unit risk estimate based on animal bioassays is
only an approximate indication of the absolute risk in populations exposed to
known carcinogen concentrations. First, there are important species differ-
ences in uptake, metabolism, and organ distribution of carcinogens, as well
as species differences in target site susceptibility, immunological responses,
hormone function, dietary factors, and disease. Second, the concept of equiv-
alent doses for humans compared to animals on a mg/surface area basis is vir-
tually without experimental verification as regards carcinogenic response.
Finally, human populations are variable with respect to genetic constitution
and diet, living environment, activity patterns, and other cultural factors.
The unit risk estimate can give a rough indication of the relative potency
of a given agent as compared with other carcinogens. Such estimates are, of
course, more reliable when the comparisons are based on studies in which the
5-2
-------
test species, strain, sex, and routes of exposure are similar.
The quantitative aspect of carcinogen risk assessment is addressed here
because of its possible value in the regulatory decision-making process, e.g.,
In setting regulatory priorities, evaluating the adequacy of technology-based
controls, etc. However, the imprecision of presently available technology for
estimating cancer risks to humans at low levels of exposure should be recog-
nized. At best, the linear extrapolation model used here provides a rough but
plausible estimate of the upper limit of risk from exposure to a unit concen-
tration of gasoline vapor (I.e., with this model it is not likely that the true
risk would be much more than the estimated risk, but it could be considerably
lower).
The risk estimates in this paper relate only to exposure to gasoline
vapor. Risks related to the entire range of compounds that may be present in
air are not estimated here.
5.1. PROCEDURES FOR THE DETERMINATION OF UNIT RISK
5.1.1, Low^lDose! Extrjpolajbji onJModel
The mathematical formulation chosen to describe the linear nonthreshold
dose-response relationship at low doses is the linearized multistage model.
This model employs enough arbitrary constants to be able to fit almost any
monotonically increasing dose-response data, and it incorporates a procedure
for estimating the largest possible linear slope (In the 95% confidence limit
sense) at low extrapolated doses that is consistent with the data at all dose
levels of the experiment.
Let P(d) represent the lifetime risk (probability) of cancer at dose d._
The multistage model has the form:
5-3
-------
P(d) = 1 - exp C-(q0 + qxd + q^2 + ... + qkdk)]
where
qi >.0, i = 0, 1, 2, .... k
Equlvalently,
Pt(d) = 1 - exp [-(q^ + q2d2 + ... + qkdk)]
where
P(d) - P(0)
Pt(d) -
1 - P(0)
is the extra risk over background rate in the animal control group at dose d.
The point estimate of the coefficients q-j , i = 0, 1, 2, ..., k» and con-
sequently, the extra risk function, Pt(d), at any given dose d, is calculated
by maximizing the likelihood function of the data. ,At low doses, upper 95%
confidence limits on the extra risk and lower 95% confidence limits on the dose
producing a given risk are determined from a 95% upper confidence limit, q^,
on parameter qj« Whenever q^ > 0, at low doses the extra risk Pt(d) has approx-
imately the form P^(d) = q^ x d. Therefore, q^ x d is a 95% upper confi-
dence limit on the extra risk and R/q^ is a 95% lower confidence limit on the
dose, producing an extra risk of R. Let LQ be the maximum value of the log-
if
likelihood function. The upper-limit q^ is calculated by increasing q^ to a
value q^ such that when the log-likelihood is remaximized subject to this fixed
•it
value q for the linear coefficient, the resulting maximum value of the log-
5-4
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likelihood LI satisfies the equation:
2 (L0 - LI) • 2,70554
where 2.70554 is the cumulative 90% point of the chi-square distribution with
one degree of freedom, which corresponds to a 95% upper-limit (one-sided).
This approach of computing the upper confidence limit for the extra risk P-t(d)
is an improvement on earlier models. The upper confidence limit for the extra
risk calculated at low doses is always linear. This is conceptually consistent
with the linear nonthreshold concept discussed earlier. The slope, q^» is
taken as an upper-bound of the potency of the chemical in inducing cancer at
low doses.
In fitting the dose-response model, the number of terms in the polynomial
is chosen equal to (h-1), where h is the number of dose groups in the experi-
ment, including the control group.
Whenever the multistage model does not fit the data sufficiently well,
data at the highest dose is deleted and the model is refit to the rest of the
data. This is continued until an acceptable fit to the data is obtained. To
determine whether or not a fit is acceptable, the chi-square statistic
1=1
is calculated where N.J is the number of animals in the i dose group, X^
is the number of animals in the 1*" dose group with a tumor response, P^ is
the probability of a response in the i^1 dose group estimated by fitting the
5-5
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multistage model to the data, and h 1s the number of remaining groups. The
fit 1s determined to be unacceptable whenever X2 Is larger than the cumulative
99% point of the chi-square distribution with f degrees of freedom, where f
equals the number of dose groups minus the number of non-zero multistage co-
efficients.
5.1.2. Selection of Data
For some chemicals, several studies in different animal species, strains,
and sexes, each run at several doses and different routes of exposure, are
available. A choice must be made as to which of the data sets from several
studies to use in the model. It may also be appropriate to correct for metab-
olism differences between species and for absorption factors via different
routes of administration. The procedures used in evaluating these data are
consistent with the approach of making a maximum-likely risk estimate. They
are as follows:
1. The tumor incidence data are separated according to organ sites or
tumor types. The set of data (i.e., dose and tumor incidence) used in the
model is the set where the incidence is statistically significantly higher
than the control for at least one test dose level and/or where the tumor inci-
dence rate shows a statistically significant trend with respect to dose level.
The data set that gives the highest estimate of the lifetime carcinogenic risk,
q^, is selected in most cases. However, efforts are made to exclude data
sets that produce spuriously high risk estimates because of a small number of
animals. That 1s, if two sets of data show a similar dose-response relation-
ship, and one has a very small sample size, the set of data having the larger
sample size is selected for calculating the carcinogenic potency.
2. If there are two or more data sets of comparable size that are iden-
tical with respect to species, strain, sex, and tumor sites, the geometric mean
5-6
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of qj, estimated from each of these data sets, is used for risk assessment.
The geometric mean of numbers Aj» A2 Am 1s defined as
/ft, v fl_ y V A \*/™
\r»i A **y " • • » « ^itl'
3. If two or more significant tumor sites are observed in the same study,
and if the data are available, the number of animals with at least one of the
specific tumor sites under consideration is used as Incidence data in the model
S.I.3. Calculation of Human Equivalent Dosages
Following the suggestion of Mantel and Schneiderman (1975), it is assumed
that mg/surface area/day is an equivalent dose between species. Since, to a
close approximation, the surface area is proportional to the two-thirds power
of the weight, as would be the case for a perfect sphere, the exposure in
mg/day per two-thirds power of the weight is also considered to be equivalent
exposure. In an animal experiment, this equivalent dose is computed in the
following manner:
Let
Le = duration of experiment
le = duration of exposure
m = average dose per day 1n mg during administration of the agent (i.e.,
during le), and
W = average weight of the experimental animal
Then, the lifetime exposure is:
Le x W2/3
5-7
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5.1.3.1. Oral—Often exposures are not given 1n units of rug/day,, and it becomes
necessary to convert the given exposures into mg/day. Similarly,, in drinking
water studies, exposure is expressed as ppm in the water. For example, in most
feeding studies exposure is given in terms of ppm in the diet. In these cases,
the exposure in mg/day is:
m ~ ppm x F x r
where ppm is parts per million of the carcinogenic agent in the diet or water,
F is the weight of the food or water consumed per day in kg, and r is the ab-
sorption fraction. In the absence of any data to the contrary, r is assumed to
be equal to one. For a uniform diet, the weight of the food consumed is pro-
portional to the calories required, which in turn is proportional to the sur-
face area, or two-thirds power of the weight. Water demands are also assumed
to be proportional to the surface area, so that
m * ppm x wt'J x r
or
m
2/3
rW
As a result, ppm in the diet or water is often assumed to be an equivalent
exposure between species. However, this is not justified for the present
study, since the ratio of calories to food weight is very different in the
diet of man as compared to laboratory animals, primarily due to differences
in the moisture content of the foods eaten. For the same reason, the amount
5-8
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of drinking water required by each species also differs. It is therefore
necessary to use an empirically-derived factor, f = F/W, which is the
fraction of an organism's body weight that is consumed per day as food,
expressed as follows:
Fraction of body
weight consumed as
Speci es W ffood ^water
Man
Rats
Mice
70
0.35
0.03
0.028
0.05
0.13
0,029
0.078
0.17
Thus, when the exposure is given as a certain dietary or water concentration in
ppm, the exposure in mg/W^/3 -js
m
« -EEEJLJL = PPm x f.x W = ppm x f x W1/3
rW2/3 w2/3 w2/3
When exposure 1s given in terms of mg/kg/day = m/Wr - s, the conversion is
simply
_JL_ . s x
rW2/3
5.1.3.2. I. ni ha1at ion--Whe n exposure is via inhalation, the calculation of dose
can be considered for two cases where (1) the carcinogenic agent is either a
completely water-soluble gas or an aerosol and is absorbed proportionally to
the amount of air breathed in, and (2) where the carcinogen is a poorly water-
soluble gas which reaches an equilibrium between the air breathed and the body
5-9
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compartments. After equilibrium is reached, the rate of absorption of these
agents is expected to be proportional to the metabolic rate, which in turn is
proportional to the rate of oxygen consumption, which in turn is a function of
surface area,
5.1.3,2.1 Case 1. Agents that are in the form of particulate matter or vir-
tually completely absorbed gases, such as sulfur dioxide, can reasonably be
expected to be absorbed proportionally to the breathing rate. In this case the
exposure 1n mg/day may be expressed as:
m = I x v x r
where I » inhalation rate per day in m^, v - mg/m^ of the agent in air, and
r = the absorption fraction.
The inhalation rates, I, for various species can be calculated from the
observations of the Federation of American Societies for Experimental Biology
(FASEB, 1974) that 25 g mice breathe 34.5 liters/day and 113 g rats breathe
105 liters/day. For mice and rats of other weights, W (in kilograms), the
surface area proportionality can be used to find breathing rates in m^/day as
fol1ows:
For mice, I =0.0345 (W/0.025)2/3 m3/day
For rats, I - 0.105 (W/0.113)2/3 m3/day
For humans, the value of 20 m^/day is adopted as a standard breathing rate
(International Commission on Radiological Protection, 1977).* The equivalent
*The average breathing rate is 10^ cm^ per 8-hour workday and 2 x 10? cm^ in 24
hours.
5-10
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exposure in mg/W^/S f0p these agents can be derived from the air intake data
in a way analogous to the food intake data. The empirical factors for the air
intake per kg per day, i = I/W, based upon the previously stated relationships,
are tabulated as follows:
Species M 1 = I/W
Man 70 0.29
Rats 0.35 0.64
Mice 0.03 1.3
Therefore, for particulates or completely absorbed gases, the equivalent expo-
sure in mg/W2/3 is
m Ivr iWvr 1/3
ss _____ 9 ___™_ s •JW yp
w2/3 w2/3 w2/3
In the absence of experimental information or a sound theoretical argument
to the contrary, the fraction absorbed, r, is assumed to be the same for all
species.
5.1.3.2.2. Case 2. The dose in mg/day of partially soluble vapors is propor-
tional to the Og consumption, which 1n turn is proportional to W2/r^ and is also
proportional to the solubility of the gas in body fluids, which can be expressed
as an absorption coefficient, r, for the gas. Therefore, expressing the Og
consumption as 02 = k W2^, where k is a constant independent of species, it
follows that:
m = k W2/3 x v x r
5-11
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or
m
2/3
W
As with Case 1, in the absence of experimental information or a sound theoret-
ical argument to the contrary, the absorption fraction, r, is assumed to be the
same for all species. Therefore, for these substances a certain concentration
in ppm or g/m3 in experimental animals is equivalent to the same concentra-
\
tion in humans. This is supported by the observation that the minimum alveolar
concentration necessary to produce a given "stage" of anesthesia is similar in
man and animals (Dripps et a!., 1977). When the animals are exposed via the
oral route and human exposure is via inhalation or vice versa, the assumption
is made, unless there is pharmacoklnetic evidence to the contrary, that absorp-
tion is equal by either exposure route.
5,1,4. Calculation of the Unit Risk from Animals
The risk associated with d mg/kg2/3/day is obtained from the linearized
multistage model and, for most cases of interest to risk assessment, can be
adequately approximated by P(d) =1 - exp (-q^d). A "unit risk" in units X
is simply the risk corresponding to an exposure of X = 1. This value is esti-
mated by finding the number of mg/kg2/3/day that corresponds to one unit of X,
and substituting this value into the above relationship. Thus, for example, 1f
X is in units of g/m3 in the air, then for case 1, d = 0.29 x 701/3 x 10~3
mg/kg2/3/day, and for case 2, d = 1, when g/m3 is the unit used to compute
parameters in animal experiments.
If exposures are given in terms of ppm in air, the following calculation
may be used, assuming sea level barometric pressure and a temperature of 24°C:
5-12
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1 ppm - 0.041 x molecular weight
Note that an equivalent method of calculating unit risk would be to use mg/kg
for the animal exposures, and then to increase the j*n polynomial coefficient
by an amount:
(Wh/Wa)J/3 j - 1, 2, .... k,
and to use mg/kg equivalents for the unit risk values.
5.2. LIFETIME RISK ESTIMATES
5.2.1. Data Aval 1 able for Rlsjc Estimatl on
The chronic inhalation study of unleaded gasoline vapor conducted by the
International Research and Development Corporation (IRDC, 1983; MacFarland et
al., 1984) and sponsored by the American Petroleum Institute (API) 1s the only
study that can be used to derive the carcinogenic potency of unleaded gasoline
vapor. Tables 5-1 and 5-2 present dose-response data used in these calcula-
tions. The data in Table 5-2 were taken from Tables 23 and 24 of Volume 6 of
the API report. All of the tumors reported in Tables 5-1 and 5-2 were observed
after 18 months of study, with the exception of one kidney adenoma detected in
the high-dose group at 18 months.
5.2.2. Choices of Low-Dose Extrapolation Models
In addition to the multistage model currently used by the CAG for low-
dose extrapolation, estimates of risk from exposure to gasoline vapor were
also determined using two other models (the problt and the Welbull models).
These models cover almost the entire spectrum of risk estimates that could be
generated from existing mathematical extrapolation models. These models are
5-13
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TABLE 5-1. INCIDENCE RATES OF TOTAL KIDNEY TUMORS IN MALE FISCHER 344 RATS
EXPOSED TO UNLEADED GASOLINE VAPOR
Experimental dose (ppm)
0
67
292
20S6b
Standardized
lifetime dose (ppm)a
0
11.96
52.14
367.14
Incidence rate0
0/49
1/59 (1.7%)d
5/56 (8.91)
7/45 (15.6%)d
aThe dose in ppm is assumed to be equivalent between humans and animals. Since
the doses were given only 6 hours/day and 5 days/week, the lifetime dose is
calculated by multiplying the factor (5 x 7) x (6/24) to each of the experi-
mental doses.
"The data from this group were not used in the calculation.
^Turner Incidence diagnosed at termination or in rats that died after 18 months.
"Of the 7 tumors listed in the high-dose group, one was an adenoma that was
detected at 18 months.
SOURCE: MacFarland et al., 1984.
TABLE 5-2. INCIDENCE RATES OF HEPATOCELLULAR TUMORS IN FEMALE B6C3F1 MICE
EXPOSED TO UNLEADED GASOLINE VAPOR
Experimental
dose (ppm)
0
67
292
2056
Standardized
lifetime dose (ppm)
11.96
52.14
367.14
Carci noma/adenoma
incidence rate
8/57 (14.0%)
10/52 (19.2%)
13/57 (22.8%)
28/56 (50.0%)
Carcinoma
incidence rate
7/57 (12.3%)
6/52 (11.5%)
9/57 (15.8%)
20/56 (35.7%)
SOURCE: IRDC, 1983.
5-14
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generally statistical 1n character, and are not derived from biological argu-
ments, except for the multistage model, which has been used to support the
somatic mutation hypothesis of carcinogenesis (Armitage and Doll, 1954;
Whittemore, 1978; Whittemore and Keller, 1978). The main difference among
these models is the rate at which the response function, P(d), approaches zero
or P{0) as dose, d, decreases. For instance, the probit model would usually
predict a smaller risk at low doses than the multistage model because of the
difference of the decreasing rate 1n the low-dose region. However, it should
be noted that one could always artificially give the multistage model the same
(or even greater) rate of decrease as the probit model by making some dose
transformation and/or by assuming that some of the parameters in the multi-
stage model are zero. This, of course, is not reasonable without knowing, a
priori, what the carcinogenic process for the agent is. Although the multi- .
stage model appears to be the most reasonable or at least the most general
model to use, the maximum likelihood estimate generated from this model does
not help to determine the shape of the dose-response curve beyond experimental
exposure levels. Furthermore, maximum likelihood estimates at low doses ex-
trapolated beyond experimental doses could be unstable depending on the amount
of the lowest experimental dose; the upper-bound estimates from the multistage
model at low doses are relatively more stable than maximum likelihood esti-
mates. The upper-bound estimate can be taken as a plausible estimate at low
doses if the true dose-response curve is actually linear. The upper-bound
estimate means that the risks are not likely to be higher, but could be lower
if the compound has a concave upward dose-response curve or a threshold at low
doses. Because the estimated risk 1s a probability conditional to the assump-
tion that an animal carcinogen 1s also a human carcinogen, the actual risk
could range from a value near zero to an upper-bound estimate.
5-15
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5.2.3. Calculation of Unit Risk (Risk at 1 ppm)
In the calculation of unit risk, ppm in air is assumed to be equivalent
between animals and humans (see 5.1.3.2.2. Case 2). The data from the high-
est dose group in Table 5-1 have been excluded from the calculation because
the model does not fit well if these data are included (see 5.1.1.). Further-
more, the data seem to indicate the toxic effect in the highest dose group
because only two-thirds of the animals survived beyond 18 months. Using the
tumor incidence data and the corresponding lifetime dose presented in Tables
5-1 and 5-2, the cancer risks at 1 ppm are calculated by means of the multi-
stage model. The results are presented in Table 5-3. Both the 95% upper-bound
estimate and the maximum likelihood estimate are given. Because the maximum
likelihood estimate of the linear component in the multistage model 1s not zero,
the upper-bound estimate is only about two times the corresponding point esti-
mate. The cancer risk estimates in Table 5-3 can be used to represent the
carcinogenic potency of unleaded gasoline vapor. The kidney data in rats and
the combined hepatocellular adenoma/carcinoma data in mice are closely similar,
spanning a range from 2.1 x 10~^ to 3.5 x 10"^. This range represents one mea-
sure of uncertainty in the upper limit of potency, the lower limit being zero
potency,
5.2.4. Comparison of Risk Estimates by DifferentLow-Dose ExtrapolationModels
For comparison, the probit and the Wei bull models are also used to calcu-
late cancer risks at various dose levels. The results of these calculations
are presented in Table 5-4. The maximum likelihood estimates of the parameters
in each model are presented in Appendix A. The results shown in Table 5-4
indicate that all three of the models predict comparable risks (within an order
of magnitude) at 1 ppm, but the difference becomes greater as the dose becomes
smaller. For Instance, on the basis of hepatocellular tumors, the multistage
5-16
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TABLE 5r3. ESTIMATES OF CARCINOGENIC POTENCY DUE TO EXPOSURE TO
1 ppm OF UNLEADED GASOLINE VAPOR
Data base
qi 95%
upper-bound
estimate
Maximum
likelihood
estimate
(1) Kidney tumor 1n
male rats
(2) Hepatocelluar
carcinoma/adenoma
in female mice
Hepatocellular
carcinoma in
female mice
Geometric mean of (1) and (2)
3.1 x ID"3
2.1 x lO-3
1.4 x 10-3
2.7 x 10-3
2.0 x 10-3
1.4 x 10-3
8.5 x 1Q-4
1.7 x 10-3
5-17
-------
TABLE 5-4. 95X UPPER-SOUND (AND MAXIMUM LIKELIHOOD) ESTIMATION OF LIFETIME RISK AT VARIOUS DOSE
LEVELS, USING THHEE DIFFERENT LOH-OQSE EXTRAPOLATION MODELS
ui
i
•-»
O3
Data base
Kidney timor,
male rats
Hepatocellular
carcinoma/
adenoma,
female mice
Bepatocellular
carcinoma
only, female
mice
Model
Multistage
Probit
Wei bull
Multistage
Probi t
Me i bull
Multistage
Probit
Wei bull
0.001
3.53x10-5
(2.01xlO-5)
3.10x10-1!
(7.72xlO-13)
4.71xW6
(3.36x10-7)
2. 14x10-6
(1.44x10-5)
9.77x10-11
(2.85x10-12)
1.79xlO~4
(1.94xlO-5)
1.39xlO'6
(8,53xlO-7)
6. 79x10-14
(1. 07x10-15)
9.26x10-6
(4.75xlO-7)
0.005
1.77xlO-5
(1.01x10-5)
7.45xlO-9
(2.48xlO-10)
2.l9xlO-5
(2.15x10-6)
1.07x10-5
(7.20x10-6)
1. 84x10-3
(6.91x10-10)
5.63xlO-4
(6.87x10-5)
6.95x10-5
(4.27xlO-5)
5.67x10-11
(1.09xiO-!2)
4.33x10-5
(2.52x10-6)
0.01
3.53xlO-5
(2.01xlO-5)
6.28xlO-8
(2.36xlO-9)
5.36xlO-5
(4.79xlO-fi)
2. 14x10-5
(1.44x10-5)
1. 42xlO-7
(5.97x10-9)
9. 17xlO~4
(1.18x10-4)
1.39xlO-5
(8.53xlO-6)
7.88x10-1°
(1.71x10-12)
8.38x10-5
(5. 17x10-6)
Dose in ppm
0.05
1.77xlO-4
(LOlxlO-4)
5.15x10-6
(2.74xlO-7)
2.84x10-*
(3.07xlO-5)
1. 07xlO-4
{7.20xlO-5)
9.67x10-6
(5.50x10-7)
2.81/10-3
(4.19x10-4)
6.95xlO-5
(4.27xlO-5)
1.91x10-7
(5.61xlO-9)
3.81x10-4
(2.75x10*5)
0.10
3.53x10-*
(2.01xlO-4)
2.72xlO-5
(1.72x10-6)
5.73xlO-4
(6.83x10-5)
2.14x10-4
(1.44x10-4)
4.79x10-5
(3.14x10-6)
4.53x10-3
(7.21xlO-4)
1.39xlO-4
8.53xlO-5)
1.56x10-6
(5.27xlO-8
7. 17xlO-4
(5.61xlO-5)
0.5
1.77x10-3
(l.OlxlO-3)
7.40x10-4
(?.. 39x10-5)
3.82x10-3
(4.38x10-4)
1.07xlO-3
(7.20x10-*)
1.17x10-3
(1.12x10-*)
1.34xlO-z
(2.55x10-3)
6.95x10-4
(4.27x10-4)
1.08x10-4
(5.35x10-6)
3.17x10-3
(2.99x10-4)
1.0
3.53x10-3
(2.01x10-3)
2.40x10-3
(3.02xlO-4)
5.44xlO-3
(9.74x10-*)
2.14xlO-3l
(1.44xlO-3)
3.72xlO-3
{4.24xlO-4)
2.11xlO-2
(4.38x10-3)
1.39x10-3
(8. 53x10-4)
5.13x10-4
(3.04x10-5)
5.88x10-3
(6.14xlO-4)
-------
model predicts a much higher risk than that predicted by the probit model at a
dose level of 0.001 ppm. This observation 1s not surprising, since the tangent
(slope) of the probit curve approaches zero as dose approaches zero, while the
slope of the multistage curve is linear at low doses. The risks predicted by
the Wei bull model on the basis of kidney tumors and hepatocellular carcinomas/
adenomas are higher on the entire exposure range (0.001 ppm to 1.0 ppm) than
the multistage model because the Wei bull model shows a more-than-linear dose-
response relationship, which is not considered biologically plausible. For
this reason, low-dose linearity has intuitive appeal. For example, the inci-
dence of hepatocellular tumors at the lowest experimental dose (11.96 ppm)
is 10/52, and the incidence in controls (0 ppm) is 8/57. In the absence of
knowledge as to the shape of the dose-response relationship below the lowest
experimental dose level, the only reasonable method of estimating cancer
potency without having the possibility of seriously underestimating the true
risk is to use linear extrapolation. That is, the slope (potency) is calcu-
lated by:
(10/52 - 8/57)/ll,96 = 4.3 x lQ-3/ppm
This crude estimate 1s about threefold greater than the maximum likelihood es-
timate (1.44 x 10-3/ppm) calculated from the multistage model which utilizes all
the data points, including the lowest data point used in the above calculation.
If one assumes that the dose-response curve is concave upward at low doses,
the risk calculated by the low-dose linear model can be considered an upper-
bound estimate of the true risk; 1t is the only plausible estimate that does
not have the potential for underestimating the true risk on the basis of the
data given. Any more precise estimate would require either further assump-
5-19
-------
tlons about the shape of the dose-response curve OP biological knowledge of
the mechanism of carcinogenic action.
In comparing the models in Table 5-4, it should be noted that the multi-
stage model has higher maximum likelihood estimates than the probit model for
all doses except for hepatocellular carcinoma/adenoma in female mice at 0.5 and
1.0 ppm. This result 1s attributed to the low-dose linearity characteristic of
the multistage model's prediction of the dose-response relationship. In fact,
the multistage model produces a linear relationship over the entire range of
exposure estimates (0.001 ppm to 1.0 ppm) that would be produced by emissions
of controlled and uncontrolled gasoline vapors. Based on its low-dose linear-
ity characteristic, the multistage model is selected as the model EPA should
rely upon to estimate risk of exposure to gasoline vapor because it provides
conservative estimates at low doses and an adequately conservative approxima-
tion of risk at higher doses.
5.2.5. Uncertainties of Quantitative Rjjs,k_rAssessment
5.2.5.1. Uncertainties Associated with Potency Estimates—It is well known
that different models, all of which might fit well with a given set of data
over the experimental dose range, might nevertheless predict drastically dif-
ferent responses at low doses. Gasoline vapor data are no exception. As shown
in Table 5-4, the multistage model predicts much higher risk than the probit
model at 0.001 ppm, on the basis of liver tumor incidence. The risk estimate
at low doses for unleaded gasoline vapor is calculated by using the linearized
multistage model, which is linear at low doses. The potency estimate derived
from such a model has been considered an upper-bound estimate on the assumption
that the shape of the dose-response curve 1s upwardly concave at low dose
levels. The carcinogenic potency, q^, as derived from the multistage model,
represents the 95% upper-bound confidence estimate, reflecting only the statis-
5-20
-------
tical variability of the response data.
The low-dose risk estimate derived from animal data must further be extra-
polated to humans. There are many factors that must be considered in extrapo-
lating risk from animals to humans. Included among these factors are differ-
ences between humans and animals with respect to life span, body size, genetic
variability, and pharmacokinetic effects such as metabolism and excretion
patterns. In assessing the risks of gasoline vapor, it was assumed that ppm
in air will induce the same tumor response in humans as in animals. It is
questionable, however, whether this simple assumption is capable of accounting
for all the differences between humans and the animals that were used in the
gasoline experiment of the IRDC (1983).
5.2.5.2, Uncertainties Regarding the Assumption of CarcinogenicityIn Humans
Based on Animal Data—An important but often neglected factor in quantitative
risk assessment is the weight of evidence that gasoline vapor is carcinogenic
in humans. The quantitative risk estimate derived from animal data gives only
a conditional probability of cancer on the assumption that the agent is car-
cinogenic in humans. It is not possible to test the hypothesis that all animal
carcinogens are also human carcinogens since humans have not been exposed to
most chemicals causing cancer in animals at sufficient dosages to detect a
positive response. This hypotheses, however, is strengthened by the findings
that, with very few exceptions, known human carcinogens also induce cancer in
experimental animals and by the similarities in the biology of the tumorigenic
response across the animal kingdom.
There is some evidence that induction of tumors by gasoline exposure is
unique to male rats because this response is related to kidney damage result-
ing from the reaction of gasoline hydrocarbons with an alpha-2-m1croglobulin
that only the male rat produces in large quantities. If this is true, then
5-21
-------
the assumption that gasoline vapors are carcinogenic in humans is weakened.
The CAG takes the viewpoint that the kidney of the male rat does not respond
to gasoline vapors in a unique manner for several reasons:
1. The link between acute and chronic hydrocarbon nephropathy and carcinogen-
icity is not clear, nor can it be established from the data generated in
this bioassay.
2. The kidney of experimental animals has been demonstrated to be the target
for more than 100 carcinogenic chemicals (Hard, 1976).
3. A statistically significant increase in liver tumors was detected in gaso-
line aerosol-exposed female mice with no report of accompanying pathology
(MacFarland, 1983).
4. Exposure to a synthetic fuel (RJ-5) for one year resulted in a 25% inci-
dence of alveolar carcinomas in CF-1 mice, while exposure to another syn-
thetic fuel (JP-10) resulted in adrenal tumors in 14% of tested versus 5%
of control male hamsters (McNaughton and Uddin, 1983). In the chronic
gasoline aerosol exposure (MacFarland, 1983), a renal sarcoma was reported
in an intermediate-dose female rat, while three renal neoplasms were
reported in two high-dose female mice. While none of these responses was
considered statistically significant individually (lung tumors are con-
sidered highly inducible in CF-1 mice), collectively they provide sugges-
tive evidence for induction of tumors in other organs as well as for in-
duction of kidney tumors in species other than the male rat.
5.2.5.3. Vj3tcertainities_ Associated with the Use of Potency Estimates to Predict
Individual Risks in Real-Life Exposure Patterns—The carcinogenic potency
estimate for unleaded gasoline can be used to predict the human cancer risk
from continuous gasoline exposure, subject to the uncertainties previously
discussed. The actual human exposure to gasoline vapor, however, is likely to
5-22
-------
be only a few minutes per week. The questions then arise as to whether this
exposure can be averaged over an entire week in order to arrive at a continuous
exposure estimate, and whether overestimation or underestimation of the risk of
intermittent doses would result from such averaging. The available data for
analogous situations indicate that either of the two possibilities may be true.
In studying factors modulating the cardnogenicity of benzidine, Vesselinovitch
et al. (1975) demonstrated that twice-weekly administration of benzidlne by
stomach intubation was less effective in inducing liver and harderian gland
tumors but more effective in inducing lung adenomas than the continuous (daily)
feeding of equivalent doses.
Of possible relevance in considering exposures to gasoline vapor are
studies that have been conducted on low-linear energy transfer (LET) radiation.
After reviewing all available data on radiation-induced genetic and tumori-
genic effects in plants, "simple" biological systems, animals, and humans,
the National Council on Radiation Protection and Measurements (NCRP, 1980)
concluded that, for a given total dose, the high-dose-rate exposure is more
effective than the low-dose-rate exposure in producing the response, and that
the difference in response between the two exposure patterns diminishes as the
total dose decreases. The applicability of this observation in the case of
human exposure to gasoline vapor is not known. If one assumes that gasoline
vapor has the same dose-rate effect as low-LET radiation exposure, then the
use of averaging dose would not overestimate the risk and would give a close
approximation to the true risk when the exposure level is small. In this dis-
cussion, it is assumed that the dose-response relationship obtained previously
predicts accurately the true risk when the dose is continuous.
In general, three possible circumstances can occur 1n estimating cancer
risk due to gasoline vapor exposure in real-life situations when the averaging
5-23
-------
dose is used:
1. The real-life (Intermittent) exposure pattern and the continuous (averaging
dose) exposure patterns are equally effective. In this case the risk esti-
mate is unbiased.
2. The real-life exposure pattern is more effective than the continuous expo-
sure pattern. In this case the risk is underestimated when the dose is
averaged.
3. The real-life exposure pattern is less effective than the continuous expo-
sure pattern. In this case the risk is overestimated when the dose is
averaged.
Not enough is known about the mechanism of action to state which possibility
is the most likely or to know the magnitude of either the overestimation or
the underestimation.
5.2.5.4. Uncertainties Associated with Differences 1n Compositioni of Gasoline
Vapors and Wholly Vaporized Gasoline—According to results of subchronlc stud-
ies sponsored by the API, the 0° to 145°F distillate fraction of unleaded gaso-
line as well as C4-C5 aliphatic hydrocarbons, which are the primary constituents
of this fraction, did not cause detectable nephrotoxicity in rats (IIT Research
Institute, 1985a, b). It was further shown that the 145° to 28Q°F fractions
contained most of the nephrotoxic activity and that the specific compounds
responsible for most of the toxicity were branched-chaln aliphatics 6 to 9 car-
bons in length. Since the 0° to 145°F distillate fraction is much more vola-
tile at ambient temperatures than the heavier distillates, the vapor fraction
would be expectd to contain a much greater percentage of short-chain hydrocar-
bons. Analyses of bulk liquid gasoline and vapor at various ambient tempera-
tures have shown that the percentage of hydrocarbons in the vapor fraction
equal to or greater than C6 is about 1/5 that of bulk liquid gasoline (U.S.
5-24
-------
EPA, 1980). For the most toxic components of gasoline, such as trimethylpen-
tane, the disparity is even greater. If in fact the development of nephrotox-
icity in male rats leads directly to cancer, then the quantitative assessment
of risk may be overly conservative. However, the linkage between nephrotox-
icity and cancer has not been proven. Moreover, there are no data to indicate
which fraction is responsible for induction of liver tumors in mice. Neverthe-
less, the disparity in composition of whole aerosolized gasoline used in the
chronic cancer assessment study (Haider et a!., 1984) and gasoline vapors
results in an additional degree of uncertainty.
5.2,6. Cancer Risk Attributablei to Benzene Content in Gasoline Vapor
The quantitative estimate of cancer risk from exposure to benzene has
recently been updated (U.S. EPA, 1985). The unit risk was derived for leukemia
in humans due to lifetime exposure to 1 ppm benzene in the air. Using various
models and combinations of assumptions and epidemiologic studies, 21 unit risk
estimates, ranging from 0.9 x 10~2 to 1 x 1G~*, were obtained. Based on the
criteria of using the data for all epidemiologic studies with reasonable expo-
sure information and an average value over all mathematical models believed to
be plausible, a combined risk estimate of 2.6 x 10"2 was derived. This was
taken to be the CAG's best assessment of unit risk.
To estimate the cancer incidence which could be attributed to the benzene
content of the gasoline mixture, the following assumptions were made:
1. The tumor response to benzene is additive to the response produced by
other components; that is, benzene does not act synergistically or antagon-
istically with other components.
2. A particular air concentration (measured as ppm) produces the same effect
in animals and humans.
5-25
-------
With these assumptions, the animal tumor incidence expected from the
benzene component alone, relative to the incidence expected from the mixture
is:
AR = (benzene potency/gasoline potency) x 0.02
= (2.6 x 10-2/2.7 x ID"3) x 0.02
= 0.19
where 0.02 was the fractional benzene content of gasoline in the rat study.
TWs calculation indicates that, irrespective of the tumor site, the
benzene component is expected to account for about 20% of the total response.
This small an incidence is undetectable, since 20% of the kidney cancer inci-
dence at the high dose (Table 5-1) is only 0.2 x 16% ~ 3%, which is only about
one animal out of 45 in that group. Therefore, the observed response has no
detectable benzene component.
Unfortunately, there is no evidence from the benzene or gasoline literature
to support or deny the additivity assumption. There is abundant evidence that
a carcinogen or a noncarcinogen could modify (enhance or inhibit) the carcino-
genic action of another compound. Since gasoline vapor contains more than one
chemical compound, such interactive effects are possible. Further research is
needed to Identify which specific compounds are responsible for the carcinogenic
effect and to define the factors and other chemicals which could modify their
action.
5.3. CONCLUSIONS OF THE HEALTH EFFECTS INSTITUTE REGARDING THE POTENTIAL
ADVERSE HEALTH EFFECTS OF EXPOSURE TO GASOLINE VAPORS
Both the Motor Vehicle Manufacturers Association and the EPA requested
that the Health Effects Institute (HEI) undertake a review of the issues con-
5-26
-------
earning potential adverse health effects of exposure to vapors of unleaded
gasoline. The HEI carried out this review, which has been published in a
special report (HEI, 1985). On the basis of the API-supported chronic animal
inhalation studies (MacFarland et al., 1984), the HEI concluded that wholly
vaporized gasoline is an animal carcinogen and a presumptive human carcinogen.
Taken collectively, the epideraiologic studies were considered to provide weakly
suggestive evidence, but did not provide an association between exposure to
petroleum vapors and increased kidney cancer. Thus, the available epidemic-
logic evidence was considered to neither negate nor confirm the interpretation
that gasoline vapors are a potential human carcinogen. ~
Because of the uncertainty regarding the carcinogeriicity of gasoline va-
pors in humans, the differences in composition of gasoline vapors to which
humans are exposed and the wholly vaporized gasoline used in the animal stud-
ies, and because of the different patterns of exposure in humans and experimen-
tal animals, the HEI considered the development of a meaningful and realistic
quantitative risk assessment to be very problematic. On the basis of the
available animal studies and established guidelines, the HEI agreed that the
existing data can be used to calculate an upper-bound risk factor for gasoline
vapors as the EPA has done. The HEI cautions, however, that the associated
health hazards, if any, cannot be established without additional data, and that
the actual risk may in fact be anywhere between zero and the upper bound.
5.4. SUMMARY OF QUANTITATIVE RISK ESTIMATION
Data from the API study on kidney tumors in male rats and liver adenomas
and carcinomas in female mice were used to derive an estimate of the incremen-
tal upper-limit unit risk due to continuous human exposure to 1. ppm of unleaded
gasoline. Since the animals breathed the complete mixture under laboratory
conditions, whereas humans are expected to breathe only the more volatile com-
5-27
-------
ponents of the mixture, the estimates are uncertain. The estimates from the
mouse and rat data are similar: 2.1 x 10~3 (ppm)"1 from mouse data and 3.5 x
10~3 (ppm)"1 from rat data.
The presence of 2% benzene in the unleaded gasoline mixture could theoret-
ically contribute to the response, although the mouse liver and rat kidney have
not been target organs in animal experiments with benzene. Based on those
experiments, it is estimated that the contribution of benzene to the response
observed in the API unleaded gasoline studies could be on the order of 20%.
However, there is no qualitative evidence that benzene actually is contributing
to the response.
5-28
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APPENDIX A
COMPARISON AMONG DIFFERENT EXTRAPOLATION MODELS
Three models used for low-dose extrapolation, assuming the independent
background, are:
Multistage: P(d) = 1 - exp [-(q^ •+ ... + qkdk)3
where q-j are non-negative parameters;
A + B ln(d)
Probit: P(d) » / f(x) dx
where f(.) is the standard normal probability density function; and
Weibull: P(d) - 1 - exp E-bdk]
where b and k are non-negative parameters.
The maximum likelihood estimates (MLE) of the parameters in the multistage
model are calculated by means of the program 6LOBAL82, which was developed by
Howe and Crump (1982). The MLE estimates of the parameters in the probit and
Weibull models are calculated by means of the program RISK81, which was devel-
oped by Kovar and Krewski (1981). Table A-l presents the MLE of parameters in
each of the four models.
A-l
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TABLE A-l. MAXIMUM LIKELIHOOD ESTIMATES OF THE PARAMETERS FOR
THE THREE EXTRAPOLATION MODELS BASED ON THREE DATA SETS
IN API UNLEADED GASOLINE STUDY
Data base
Kidney tumor
in male rats
Hepatocellular
carci noma/ adenoma
in female mice
Hepatocellular
carcinoma in
female mice
Multistage
model
m » 2.01 x 10"3
q2 - 0
q1 » 1.44 x 10"3
On — C|o — 0
qi • 8.53 x ID"4
q2 = 3.83 x 10~B
A
B
A
B
A
B
Probit
model
= -3.43
= 0.53
= -3.29
- 0.52
= -3.98
= 0.57
Wei bull
model
b «
k =
b »
k **
b «
k =
9.75
1.15
5.15
0.78
6.95
1.04
xlO"4
x 10"3
x 10-4
SOURCE: IRDC, 1983.
A-2
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