Registration Dossier

Toxicological information

Direct observations: clinical cases, poisoning incidents and other

Currently viewing:

Administrative data

Endpoint:
direct observations: clinical cases, poisoning incidents and other
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well-documented publication which meets basic scientific principles.
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Mortality among synthetic fiber workers exposed to glycerol polyglycidyl ether
Author:
Lanes, S. F., Rothman, K. J., Soden, K. J., Amsel, J., Dreyer, N. A.
Year:
1994
Bibliographic source:
Am J Ind Med. 1994 May; 25(5): 689-96.

Materials and methods

Study type:
other: mortality study
Endpoint addressed:
carcinogenicity
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Mortality among employees who worked at any time from 1965 to 1988 at a synthetic fibers plant was studied. The workers were exposed to a finishing agent containing glycerol polyglycidyl ether. The main route of exposure to workers was inhalation of the spray mist, although there was also skin contact.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
aerosol dispenser: not specified
Remarks:
migrated information: aerosol
Details on test material:
- Name of test material (as cited in study report): a finishing agent containing glycerol polyglycidyl ether

Method

Type of population:
occupational
Subjects:
- Number of subjects exposed: 8878
- Sex: m/f
- Age: <20 - 70+ years
- Race: white, non-white, unknown
- Demographic information: name, social security number, date of birth, race, gender, dates of hire and termination, marital status, and payroll status.
- Known diseases: not reported; the vital status of employees was ascertained.
- Other: Among the portion of the cohort for which race was available, 80% were white. Seventy percent of the employees were men. The cohort contributed 143,231 person-years over the 24-year follow-up period, with 82,144 person-years (57%) contributed by employees less than 40 years old (see Table 2 in "results").
Ethical approval:
not applicable
Remarks:
mortality study
Route of exposure:
dermal
inhalation
Reason of exposure:
unintentional, occupational
Exposure assessment:
estimated
Details on exposure:
The mortality of workers at a polyester fiber manufacturing plant in North Carolina was studied. The plant has been in operation since 1965, and in 1969 began using a finishing agent containing glycerol polyglycidyl ether. The finishing agent containing glycerol polyglycidyl ether was sprayed onto polyester fiber in the filament spindraw area of the plant, and the primary route of exposure was inhalation of the mist, although there was also skin contact. This study was initiated by the plant to measure any possible effect of exposure to glycerol polyglycidyl ether on the occurrence of cancer among employees.
Although no exposure measurements are available for most of the study period, a company report in 1988 indicated that exposure levels varied considerably within the filament spindraw area according to whether employees worked at a line that was using glycerol polyglycidyl ether and on which floor the employees worked. It is difficult to use these data to estimate individual exposures because individual work history data indicate only the department where an employee worked, but not the floor or line. Nevertheless, these data provide some perspective on exposure levels in the filament spindraw area where glycerol polyglycidyl ether ranged from 1.1 mg/m³ 8-hour time weighted average (TWA-8) to 4.8 mg/m³ (TWA-8). On lines not using glycerol polyglycidyl ether, however, exposure levels ranged from below detectable levels to 0.2 mg/m³. Exposure levels were more uniform, but somewhat lower, on the second floor, ranging from below detectable levels to 1 mg/m³.
Examinations:
Expected numbers of deaths were computed in the cohort using age-, race-, and gender-specific annual mortality rates for the United States (U.S.) population and the local county population. Since the national rates and local rates were similar, analyses using the more stable U.S. rates were used. Cohort members contributed person-time to the analysis from the date of hire until either the date of death or December 31, 1988.
Then, standardized mortality ratios (SMRs) were computed as the ratio of the number of observed deaths in the cohort to the number of deaths expected if employment were unrelated to mortality. Effect estimates were standardized for age, race, gender, and calendar time. The precision of the effect estimates was assessed by computing 95% confidence limits using a Poisson approximation.
Medical treatment:
Not applicable.

Results and discussion

Clinical signs:
Not applicable (mortality study)
Results of examinations:
The overall SMR for all causes of death combined was 0.80. For cardiovascular disease the SMR was 0.87, and for all malignant neoplasms combined the SMR was 0.92. No cancer site met our criteria of an SMR greater than 2.0 and at least five observed deaths. Among cancer sites, the largest SMR was for cancer of the central nervous system (SMR = 1.77); the SMR for cancer of the bronchus, trachea, and lung was 0.94.
Effectivity of medical treatment:
Not applicable
Outcome of incidence:
No clear carcinogenic effect of glycerol polyglycidyl ether. Mortality rates in the cohort were similar to mortality rates in the US population.

Any other information on results incl. tables

"We identified 553 deaths in the cohort of 8,878 employees. Table 1 shows the distribution of the cohort and the deaths by gender, race, and hire date. Fifty percent of the employees were hired between 1965 and 1969, and information on race was not recorded for 2,416 employees hired during these early years of plant operation.

Table 1. Distribution of Workers at a Synthetic Fiber Manufacturing Plant According to Gender, Race, Hire Date, and Vital Status (1965-1988)

 

Deceased

Alive

Total

Gender

 

 

 

Male

471

5739

6210

Female

82

2586

2668

Race

 

 

 

White

274

4930

5204

Nonwhite

41

1217

1258

Unknown

238

2178

2416

Hire date

 

 

 

1965-1969

439

4433

4872

1970-1979

101

2716

2817

1980-1988

13

1176

1189

Total

553

8325

8878

For purposes of computing expected numbers of deaths, we randomly assigned a race to each of these employees using probabilities derived from the racial distribution of the remainder of the cohort. Among the portion of the cohort for which race was available, 80% were white. Seventy percent of the employees were men. The cohort contributed 143,231 person-years over the 24-year follow-up period, with 82,144 person-years (57%) contributed by employees less than 40 years old (Table 2).

Table 2. Person-Time and Observed Deaths From All Causes by Age in 8,878 Workers at a Synthetic Fiber Manufacturing Plant (1965-1988)

Age

Person-years

Deaths

<20

1,404

3

20-29

33,714

46

30-39

47,026

68

40-49

33,757

106

50-59

18,828

152

60-69

7,388

142

70 +

1,116

36

Total

143,233

553

Thus, the cohort is young, with approximately 6% of the cohort dying during the 24-year follow-up period. Effect estimates for major categories of cause of death and for cancer sites with at least five observed deaths are shown in Table 3.

The overall SMR for all causes of death combined was 0.80. For cardiovascular disease the SMR was 0.87, and for all malignant neoplasms combined the SMR was 0.92. No cancer site met our criteria of an SMR greater than 2.0 and at least five observed deaths. Among cancer sites, the largest SMR was for cancer of the central nervous system (SMR = 1.77); the SMR for cancer of the bronchus, trachea, and lung was 0.94.

Table 3. Observed and Expected Deaths and Standardized Mortality Ratios (SMR) From Cohort Analyses for Selected Causes of Death Among 8,878 Workers at a Synthetic Fiber Manufacturing Plant (1965-1988)

Cause of death

Observed

deaths

Expected

deaths

SMR

95% Confidence

limits

All causes

553

691.89

0.80

0.73, 0.87

Cardiovascular disease

175

200.40

0.87

0.75, 1.01

External causes

121

140.39

0.86

0.72, 1.03

Malignant neoplasms

150

162.68

0.92

0.78, 1.08

Large intestine

12

12.85

0.93

0.48, 1.63

Pancreas

8

7.33

1.09

0.47, 2.15

Bronchus, trachea, and lung

47

50.10

0.94

0.69, 1.25

Breast

12

11.43

1.05

0.54, 1.83

Prostate

5

4.78

1.05

0.34, 2.44

Kidney

6

3.58

1.68

0.62, 3.65

Central nervous system

10

5.66

1.77

0.85, 3.25

Leukemia

7

6.24

1.12

0.45, 2.31

Other non-Hodgkin's lymphopoietic

7

5.60

1.25

0.50, 2.57

We examined effect estimates according to duration of employment, time since first employment (“latency”), and calendar year. For most cancer sites, stratification by these factors revealed no apparent pattern or trend toward greater effect estimates among employees with longer employment or time since first employment. Cancers of the central nervous system (ICD-9 191-192) and other lymphopoietic tissues (ICD-9 202-203) occurred more frequently during the last few years of follow-up. Four of the 10 deaths from cancer of the central nervous system, occurred among employees with fewer than 10 years of employment and less than 10 years since first employment (SMR = 1.71), while there was a similar excess for employees with 10 or more years of employment (SMR = 2.2). All but one of the seven deaths from cancer of other lymphopoietic tissue, however, occurred among employees with at least 10 years of employment (SMR = 3.6), and three of these deaths occurred after at least 20 years since first employment (SMR = 13.6). Using employment as an indicator of exposure is a limitation of these analyses that we addressed in the case-control analyses.

Each of the cancers of the central nervous system was a brain cancer, and the cancers of other lymphopoietic tissues were lymphomas and myelomas. We included brain cancer deaths and deaths from lymphoma and myeloma in case-control analyses because cohort analyses revealed possible relations of these outcomes with duration of employment or latency. Lung cancer was selected for case-control analyses because inhalation is the primary route of exposure. We assembled work histories for 47 lung cancer deaths, 8 brain cancer deaths, 7 deaths from lymphoma and myeloma, and 3 10 controls. For each case, we selected controls from cohort members who were alive at the time the case died and who shared the same year of birth as the case. We then computed, for cases and controls, durations of employment in the spindraw areas where exposure to glycerol polyglycidyl ether occurred. Since dates of department assignments were missing for a small number of cases (n = 6) and controls (n = 42), sometimes we could not tell when an employee transferred between an exposed department and an unexposed department, so we computed the minimum duration of exposure. We classified duration of exposure in 5-year categories, and we evaluated induction time by examining risk among employees who experienced exposure at least 10 years before the date of death. Unfortunately, among employees with at least 5 years of exposure, the data were too sparse to estimate effect estimates after simultaneous stratification by induction time and duration of exposure.

The relative risk (RR) estimate for brain cancer for employees with up to 5 years of exposure was 0.58 (95% confidence limit (CL) = 0.13, 2.52; Table 4).

Table 4. Rate Ratio Estimates and 95% Confldence Limits From Case-Control Analyses for Selected Cancer Sites by Duration of Exposure to Glycerol Polyglycidyl Ether at a Synthetic Fiber Manufacturing Plant (1965-1988)

Cancer site

Duration of exposure (years)

>0-5

>5-10

>10

Brain

 

 

 

RR

0.58

*

*

95% CL

0.13, 2.52

 

 

Lung

 

 

 

RR

1.74

0.74

*

95% CL

0.87, 3.48

0.16, 3.33

 

Lymphoma and myeloma

 

 

 

RR

0.73

3.46

10.0

95% CL

0.08, 6.73

0.28, 42.2

0.91, 110

RR, relative risk; CL, confidence limits.

*Data insufficient for effect estimation.

No subject who died of brain cancer was exposed for longer than 5 years. The RR estimate for lung cancer for employees with up to 5 years of exposure was 1.74 (95% CL = 0.87, 3.48), and the RR estimate for more than 5-10 years of exposure was 0.74 (95% CL = 0.16, 3.33). No subject who died of lung cancer was exposed for more than 10 years. The RR estimates for lymphoma and myeloma were 0.73 (95% CL = 0.08,6.73) for up to 5 years of exposure, 3.46 (95% CL = 0.28, 42) for more than 5-10 years of exposure, and 10.0 (95% CL = 0.91, 110) for greater than 10 years of exposure, with only two deaths in this latter duration category".

Applicant's summary and conclusion

Conclusions:
"In this first analysis of this cohort of synthetic fiber workers, we identified no clear carcinogenic effects of glycerol polyglycidyl ether. In particular, deaths from lung cancer appeared to be unrelated to exposure. An association for lymphoma and myeloma was based on only seven cases, although risk estimates increased with duration of exposure. Any interpretation needs to acknowledge that the cohort is still young and the number of deaths for most categories of cause of death is small. Potential carcinogenic effects on hematopoietic tissues and other sites will receive further scrutiny as the cohort ages and effects can be estimated after longer induction times".
Executive summary:

Mortality was studied among 8,878 employees who worked at any time from 1965 to 1988 at a synthetic fibers plant in North Carolina that used a finishing agent containing glycerol polyglycidyl ether. Some glycidyl ethers are mutagenic and tumorigenic in laboratory animals. The main route of exposure to workers was inhalation of the spray mist, although there was also skin contact. The study was initiated by the plant to measure any possible effect of exposure to glycerol polyglycidyl ether on the occurrence of cancer among employees. Expected numbers of deaths were computed in the cohort using age-, race-, and gender-specific annual mortality rates for the United States (U.S.) population and the local county population. Since the national rates and local rates were similar, analyses using the more stable U.S. rates were used. Cohort members contributed person-time to the analysis from the date of hire until either the date of death or December 31, 1988. Then, standardized mortality ratios (SMRs) were computed as the ratio of the number of observed deaths in the cohort to the number of deaths expected if employment were unrelated to mortality. Effect estimates were standardized for age, race, gender, and calendar time. The precision of the effect estimates was assessed by computing 95% confidence limits using a Poisson approximation.

There were identified 553 deaths in the cohort and the standardized mortality ratio (SMR) from all causes of death combined was 0.80. For most causes of death, mortality rates in the cohort were similar to mortality rates in the U.S. population. Among categories with at least five observed deaths, the largest effect estimate was for cancer of the central nervous system (SMR = 1.77), and the SMR for lung cancer was 0.94. The cancer categories of central nervous system (brain) and “other” lymphopoietic cancers (lymphoma and myeloma) showed weak associations with duration of employment. In case-control analyses in which work history data were utilized to compute effect estimates by duration of exposure, no increased risk of lung cancer or brain cancer among employees with more than 5 years of exposure was found. Effect estimates for lymphoma and myeloma tended to increase with duration of exposure, although there were only seven deaths in this category and the effect estimates were very imprecise. To date, this study has identified no clear carcinogenic effect of glycerol polyglycidyl ether, but plausible induction periods have not yet elapsed. The cohort should continue to be monitored to obtain more precise estimates after moderate or long induction times.