Diethyl sulphate

Epidemiological data

Administrative data

Endpoint:

epidemiological data

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study performed by NIOSH

Data source

Reference

Reference Type:

publication

Title:

Case-Control Study of Gliomas of the Brain among Workers Employed by a Texas City, Texas Chemical Plant

Author:

Leffingwell SS, Waxweiler R, Alexander V, Ludwig HR, Halperin W

Year:

1983

Bibliographic source:

Neuroepidemiology 2: 179-195

Materials and methods

Study type:

case control study (retrospective)

Endpoint addressed:

carcinogenicity

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

A case-control study examined possible associations between gliomas of the brain and job title, departmental employment history, chemical exposure history, geographic location within plant, dates of employment, and residence.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Diethyl sulphate

EC Number:

200-589-6

EC Name:

Diethyl sulphate

Cas Number:

64-67-5

Molecular formula:

C4H10O4S

IUPAC Name:

diethyl sulfate

Details on test material:

no data

Method

Details on study design:

Case Identification
A total of 23 possible cases were identified: the company documented 12 cases from death certificates in their possession; lists of all adult males who were residents of surrounding counties and who died of malignant brain tumors between 1950 and 1977 were matched with company employment records, yielding 4 additional cases; another 3 cases became ill and died during the course of the study; and 4 additional deceased cases were found in the course of completing the cohort mortality study. We were able to obtain medical records for 20 of the possible cases and tissue specimens for 10.
The Armed Forces Institute of Pathology (AFIP) reviewed the tissue specimens. Where different diagnoses were recorded for the same patient, AFIP reviews were ranked first, autopsy reports second, surgical pathology reports third, diagnosis from the hospital chart fourth, and death certificate diagnosis last; the highest-ranked diagnosis was used for this study.
Since gliomas are carcinomas, arising from ectodermal tissue of the neural crest, while meningiomas arise from mesodermal embryonic tissue, consideration was limited in this study to the 17 gliomas among the 23 former employees with death certificate diagnoses of brain tumor. This eliminated 1 case with a metastatic brain tumor from an unknown site, 1 who had been thought clinically to have a brain tumor but was found at autopsy to have a congenital malformation and no tumor, and 4 meningiomas.

Selection of Control Subjects
For each case, a pool of matched potential controls was drawn from the cohort of all people ever employed at the plant. Matching criteria were: race and sex matched the case; year of birth was within 3 years of the case's; date of first employment at the Texas City plant for the control was before that of the case, but year of first employment at the Texas City plant was not earlier than 3 years before the case's; the date the control was last employed was later than the case's last date of employment; the control, if dead, must not have died of a malignancy. For each case, 6 controls were then drawn by random number from the pool of employees meeting these criteria. No control was used for more than 1 case. Some cases and controls had prior experience in refineries or chemical plants, but the information available was insufficient for analysis.

Data Collection
For each case and control, plant personnel completed coding sheets containing demographic data, date of each new job title or department code, job code, department code, date of each layoff, date of final termination (if no longer employed at the plant), and vital status (when known). NIOSH/OSHA researchers independently verified the accuracy of the coding.
Plant personnel provided translations for the job and department codes, indicated which department codes formed larger major department groups, and provided a list of chemicals used, produced, or redistributed in each department group. A 'department group' is an operational unit of the plant manufacturing related products and within which employees often remained over fairly long periods. The departmental coding schemes used for accounting purposes within the plant have changed over the years, so a common list tracing the history of each department was prepared.
Plant engineers were able to characterize the chemical feedstocks, outputs, and intermediate products of each department through the years the plant has been in operation. Since industrial hygiene data were available only for recent years and for certain compounds, the presence of a chemical in a department was equated with potential worker exposure. This assumption was clearly not always accurate, nor were exposures necessarily equal in two departments using the same chemical.

Analysis
For each job, department, major department group, or chemical exposure common to at least 4 cases, an odds ratio was calculated and tested for possible statistical significance by Mantel and Haenszel's procedure, using the matched data programs of Rothman and Boice. Analyses were conducted for periods less than 15 years before the death of the case, 15 or more years before the death of the case, and any time before the death of the case (a case exposed for greater than 15 years and dying soon after last exposure would be counted in all three periods). Since this approach is a multiple-significance testing technique which should lead by chance to the finding of approximately one statistically significant positive association, using a 90% (two-sided) confidence interval, for every 20 independent jobs, departments, or exposures considered, it is used here as an exploratory or hypothesis-generating mechanism; the probability values and confidence intervals cited throughout the paper are given only to show relative strength of associations.
Only those portions of the controls' work experiences which occurred during the time the corresponding case was employed were considered in this analysis, since the matching criteria selected controls with longer total work histories than the cases'.
Duration of exposure was examined for chemical exposures for which (a) the association with brain tumors reached statistical significance in the analyses described above or (b) previous reports suggested a possible relationship. For each chemical, cases' and controls' median months of potential exposure 15 years or more before death of the case were tabulated and a rank-sum test was performed . Employees with no exposure were excluded.
Workers in a department nominally unexposed to a particular chemical could be exposed to toxic airborne vapors or dusts from an adjacent department. To assess this possibility, the years worked by each subject in each department group were tabulated, showing which department groups had about the expected 1:6 ratio of case to control years, which groups had disproportionately more case-years, and which had fewer. This information was plotted on a map of the plant, which was inspected for clusters.

Non-Work Factors
The possibility was considered that the excess risk at the plant might be a reflection of an excess in the communities around the plant rather than a problem intrinsic to the plant. A case-location service was retained to determine past places of residence for the cases and controls and additional information was obtained through review of medical records retained at the plant. Analyses were conducted for communities in which at least 5 cases had lived, using a division of 'never lived' versus 'never lived' in the community for periods. 15 or more years before the death of the case, less than 15 years before the death of the case, and any time before the death of the case. The analysis of residence used all addresses up to the date of the case's death. A two-sided 90% confidence interval was calculated to display the strength of association.

Exposure assessment:

estimated

Results and discussion

Results:

The greatest apparent risks were associated with exposure to carbon dioxide, diethyl sulfate, diethylene glycol, ethanol, ethylene, isopropanol, methane, tetraethylene glycol, and vinyl acetate; with first employment in the 1940s or early 1950s; and with residence in La Marque .

Strengths and weaknesses:

While some of the associations with chemicals found could be considered weak evidence of carcinogenicity, none was conclusive. There are wide confidence intervals around all of the odds ratios given; therefore, differences between odds ratios should be interpreted cautiously.

Any other information on results incl. tables

Frequencies of exposure and odds ratios for potential chemical exposures

Work period	Maintenance men*
	Excluded			Counted as exposed
	E/UE	R(M-H)	90% CI on R(M-H)	E/UE	R(M-H)	90% CI on R(M-H)
0-14	2/5	4.43	0.54-36.20	8/5	1.19	0.45-3.15
15+	3/6	4.87	1.05-22.53	9/6	0.75	0.27-2.21
ever	4/7	2.10	0.57-7.73	11/6	1.13	0.45-2.81

R_(M-H)= Mantel-Haenszel odds ratio estimate;

90% CI = 90% confidence interval;

E = exposed; UE = unexposed.

*Maintenance employees who also worked in other departments without exposure counted as unexposed.

 0-14 = work less than 15 years before death of case;

15+ = work 15 or more years before death of case.

Caseswith work experience in both the 0- to 14-year and 15+ year time periods are counted in each group

Median months of exposure to selected chemicals (15 years or more before deathof case; employees with no exposure excluded)

Time in maintenance department
Excluded		Counted as exposed
Cases/control	Z*	Cases/control	Z*
7/58	-1.51	50/80	0.11

The expected value of the sum is n₁(n₁+n₂+ 1)/2 with variance = n₁n₂(n₁+n₂+1)/12. '[(observed rank-sum)-(predicted rank-sum)]/(predicted variance);

* z > 1.96 implies p < 0.05

Unmatched odds ratios for combinations of exposure to selected substances and LaMarque residence

Time	Maintenance men
	Excluded				Counted as exposed
	Exp-LaM-(A)	Exp+LaM- (B)	Exp-LaM+ (C)	Exp+LaM+ (D)	Exp-LaM-(A)	Exp+LaM- (B)	Exp-LaM+ (C)	Exp+LaM+ (D)
0-14	1.00	4.89*	4.40*	0.00	1.00	1.81	8.40	4.31
15+	1.00	3.67*	5.50*	3.67*	1.00	0.36	6.25*	4.17
ever	1.00	3.63	24.17*	5.80*	1.00	1.33	12.80*	7.00*

Maintenance employees who also worked in other departments without exposure counted as unexposed.Except where otherwise indicated, all comparisons are to the unexposed/never lived incategory.

Column B may be interpreted as the effect of chemical exposure alone,

column C as the effect ofresidence alone, and

column D as the effect of both.

Exp- = never exposed to the chemical; Exp+ = ever exposed to the chemical; LaM- = never lived in; LaM+ = ever lived in;

*Differs from column A; Fisher's exact test, p < 0.05.

Applicant's summary and conclusion

Conclusions:

The greatest apparent risks were associated with exposure to carbon dioxide, diethyl sulfate, diethylene glycol, ethanol, ethylene, isopropanol, methane, tetraethylene glycol, and vinyl acetate; with first employment in the 1940s or early 1950s; and with residence in La Marque .

Executive summary:

A petrochemical plant had elevated standardized mortality ratios for neoplasms of the brain. A case-control study examined possible associations between gliomas of the brain and job title, departmental employment history, chemical exposure history, geographic location within plant, dates of employment, and residence. The greatest apparent risks were associated with exposure to carbon dioxide, diethyl sulfate, diethyleneglycol, ethanol, ethylene, isopropanol, methane, tetraethylene glycol, and vinyl acetate;with first employment in the 1940s or early 1950s, and with residence in La Marque. No significant differences between cases and controls were apparent in duration of exposure to any of these chemicals.