Registration Dossier

Administrative data

Endpoint:
epidemiological data
Adequacy of study:
key study
Study period:
unclear - retrospective study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific standards, no GLP, acceptable for assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1987
Report Date:
1987

Materials and methods

Study type:
cohort study (retrospective)
Endpoint addressed:
repeated dose toxicity: inhalation
carcinogenicity
Principles of method if other than guideline:
Cohort or nested case-control analysis of four health outcomes: lung cancer incidence; lung cancer deaths; chronic respiratory disease; chest X-ray abnormalities consistent with pneumoconiosis among workers exposed to titanium dioxide and/or titanium tetrachloride.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:

Exposure to titanium tetrachloride and/or titanium dioxide during manufacture of the dioxide. No further details given in report.

Method

Type of population:
occupational
Ethical approval:
not specified
Details on study design:
HYPOTHESIS TESTED (if cohort or case control study): To determine whether workers exposed to titanium dioxide or titanium tetrachloride had significantly higher risks of lung cancer, chronic respiratory disease or pulmonary fibrosis that referent groups


METHOD OF DATA COLLECTION
- Type: work history records and medical records from the two plants; Du Pont Cancer Registry; Du Pont Mortality Registry; Company Accident and Health Insurance Registry; chest radiographic examinations.
- Details:

STUDY PERIOD: cohorts for mortality 1935-1983; cohorts for cancers and chronic respiratory disease incidence 1956-1985

SETTING: occupational - two unidentified Du Pont plants: one using the sulphate process (1935-1974) and the chloride process (1948-date of report); the other using just the chloride process (1963-date of report).

STUDY POPULATION
- Total population (Total no. of persons in cohort from which the subjects were drawn): 2477
- Selection criteria: male, wage roll employees, employed for more than 1 year prior to 1 Jan 1984. (Numbers of female and salary roll employees were said to be too small to "yield statistically stable results".)
- Total number of subjects participating in study: TiCl4 969 exposed, 1508 non-exposed. TiO2 1576 exposed, 901 non-exposed.
- Sex/age/race: male (no further details)
- Smoker/nonsmoker: smoking status/history not presented

COMPARISON POPULATION
- Type: State registry / Regional registry / National registry / Control or reference group / Other comparison group: "Du Pont Company rates" (full details not given); US white male rates (no further details)

HEALTH EFFECTS STUDIED
- Disease(s): lung cancer; chronic respiratory disease; pulmonary fibrosis
- Diagnostic procedure: records (Du Pont Registry, Du Pont Accident and Health Insurance Registry); chest radiographic examinations.

OTHER DESCRIPTIVE INFORMATION ABOUT STUDY: Chest radiographs used to detect pulmonary fibrosis, were read blind by two certified B-reader radiologists. A third was consulted when there was disagreement.
Exposure assessment:
estimated
Details on exposure:
TYPE OF EXPOSURE:
Occupational

TYPE OF EXPOSURE MEASUREMENT: Area air sampling / Personal sampling / Exposure pads / Biomonitoring (urine) / Biomonitoring blood / other:
No monitoring data were available at either plant for TiO2 before 1975 (no mention of TiCl4 monitoring). Exposure Classifcation Committtess at both plants evaluated exposures to TiO2 for every job, as well as exposures to other chemicals that might have a confounding effect (TiCl4, pigmentary potassium titinate, asbestos). Exposure potential for each job was assessed for each of these four materials. (See tables 1 and 2).

EXPOSURE LEVELS:
Where no monitoring was undertaken the ranges used to quantify exposures are given in Table 1.

EXPOSURE PERIOD: exposure durations were grouped by quartile as per Table 2.

POSTEXPOSURE PERIOD: -

DESCRIPTION / DELINEATION OF EXPOSURE GROUPS / CATEGORIES:
See tables 1 and 2.
Statistical methods:
A "90%" acceptance range" was given for 'expected' numbers such that the probability under the null hypothesis of obtaining a number that exceeds the high end of the range or is less than the low end of the range is is less than 0.05.

Results and discussion

Results:
CANCER INCIDENCE (see tables 3 and 4 below).

TiCl4: Observed all cancer cases among the TiCl4-exposed cohort were significantly higher than expected (30 observed: 20.7 expected; significant at 0.05 probability level). The difference between observed and expected lung cancer cases (8 observed: 4.9 expected) was not statistically significant. Nested case-control analyses (16 lung cancer cases, 898 controls) found no statistically significant association between lung cancer risk and TiCl4 exposure (odds ratio (OR) 2.0), after adjusting for TiO2, PKT or asbestos exposure, or age (no details are given in the report). There was no clear association between the adjusted OR for lung cancer deaths and TiCl4 time-weighted average exposure levels (data not included in tables below).

TiO2: Observed all cancer cases in the TiO2-exposed cohort was also slightly higher than expected (38 O: 32.6 E), as was the number of lung cancer cases (8 O: 7.7 E); neither difference achieved statistical significance. Nested case-control analyses (16 lung cancer cases, 898 controls) found no statistically significant association between lung cancer risk and TiO2 exposure (OR 0.6), after adjusting for TiCl4, PKT or asbestos exposure, or age (no details given). There was no clear association between the adjusted OR for lung cancer deaths and TiO2 time-weighted average exposure levels (data not included in tables below).

MORTALITY (see tables 5-7 below).

TiCl4: Deaths from all causes for this exposure group were lower than expected compared to US white male mortality rates but higher, though not statistically significantly so, than expected, compared to “company-wide Du Pont mortality rates”. All cancers and cancers of the respiratory system or lungs were similar to or not significantly higher than expected compared to US and Du Pont rates. Diseases of the respiratory system were similar to or lower than expected based on US and Du Pont rates.

TiO2: Deaths from all causes for this exposure group were not statistically significantly different compared to US white male and Du Pont rates. All cancers and cancers of the respiratory system or lungs were lower or statistically significantly lower than expected compared to US and Du Pont rates. Diseases of the respiratory system were not significantly different than expected based on US and Du Pont rates.

Nested case-control analyses of 27 deaths from lung cancer and 331 non-cancer decedent controls found no statistically significant association with exposure to TiCl4 or TiO2, after adjustment for age and other exposures.

There was said to be no clear dose-response between level or duration of exposure to TiCl4 or TiO2 and the adjusted odds ratio for lung cancer mortality (data are given in the report relating to time-weighted average but not to exposure duration or cumulative exposure index). (These data have not been included in the tables below.)

CHRONIC RESPIRATORY DISEASE (CRD) (see table 8 below)
Eighty eight CRD cases and 898 controls without cancer or respiratory disease were identified from Du Pont’s Accident and Health Insurance Registry. No statistically significant association was identified between CRD and exposure to either TiCl4 orTiO2. Similarly no clear dose-response was seen between CRD and time weighted-average (TWA) exposure, exposure duration or cumulative exposure index for either chemical. (Data are given in the report for TWA exposure only – these are not reproduced below.)

CHEST X-RAY FINDINGS
Chest radiographic examinations were used to detect pulmonary fibrosis, pleural thickening/plaques and nodules among 398 employees of whom 372 had no indication of chest X-ray abnormalities. Of this group of 398, 336 were TiO2-exposed while 62 were not, and 256 were TiCl4-exposed while 142 were not. The distribution of pleural thickening (5-6% in each case) among the exposed and non-exposed groups for both chemicals did not indicate any clear association with exposure. No cases of fibrosis were identified. A small number of cases with “questionable nodules” were identified (ranging from 0.6 among the TiO2-exposed group to 3.2% among the TiO2-nonexposed group) for which further X-rays were recommended. Case-control analyses of the pleural thickening cases (22) and controls (372) found no statistically significant association with exposure to TiCl4 or TiO2 (These data are not represented by tables below.)
Confounding factors:

• Potential for exposure to other chemicals
• Overlap of TiCl4 and TiO2 exposure groups - it is unclear based on the limited examination of this reviewer the potential impact of this on some of the findings
• No details on, or control for, cigarette smoking
Strengths and weaknesses:
STRENGTHS
Comparison with Du Pont company rates was said to avoid the “healthy worker effect”.

WEAKNESSES
See Overall Remarks, below.

Any other information on results incl. tables

Table 3: Observed and expected cancer cases (1956-1985). Expected numbers based on Du Pont cancer incidence rates.

 

TiO2

TiCl4

Cancers

Observed

Expected

90% acceptance range*

Observed

Expected

90% acceptance range

All cancers**

38

32.6

24-42

30***

20.7

14-28

Respiratory system

10

9.2

5-14

9

5.8

2-10

Lung

8

7.7

3-13

8

4.9

2-9

Digestive system

10

8.9

4-14

8

4.7

0-9

Genitourinary system

10

6.3

3-11

5

3.7

0-7

Lymphohematopoietic system

3

3.7

0-7

2

2

0-5

Malignant melanoma

3

2.5

0-5

1

1.3

0-3

All other

2

2

0-5

5

3.2

0-6

*90% acceptance range is defined such that the probability under the null hypothesis of obtaining a number that exceeds the high end of the range or is less than the low end of the range is less than 0.05.

** excluding non-melanoma skin cancer

*** statistically significant at the 0.05 probability level

[Based on tables 2a and 2b of report.]

Table 4: Multiple logistic regression analyses of incident lung cancer cases according to TiO2. TiCl4, PKT (pigmentary potassium titinate) and asbestos exposures

Occupational variables in model

Adjusted odds ratio (OR)

90% confidence limits on OR

lower

upper

Referent group

1.0

-

-

TiO2

0.6

0.2

1.4

TiCl4

2.0

0.8

5.1

PKT

1.7

0.3

10.4

asbestos

1.0

0.4

2.4

16 cases, 898 controls

[Based on table 3 of report.]

Table 5: Observed and expected deaths from selected major causes (1935-1983) in TiO2 and TiCl4 cohorts. Expected numbers are based on US white male mortality rates (no further details given in the report).

 

TiO2-exposed cohort

TiCl4-exposed cohort

Observed

Expected

90% acceptance range*

Observed

Expected

90% acceptance range*

All causes

211

248.3

223-274

90**

114.6

97-132

All malignant neoplasms

39**

51.0

40-63

24

24.2

16-33

Cancer of the respiratory system

14

18.3

12-26

9

9.0

4-14

Lung cancer

9**

17.3

11-24

7

8.5

4-14

Diseases of the respiratory system

11

13.8

8-20

3

5.8

2-10

*90% acceptance range is defined such that the probability under the null hypothesis of obtaining a number that exceeds the high end of the range or is less than the low end of the range is less than 0.05.

** Statistically significant at the 0.05 probability level

[Derived from on tables 5a and 5b of report.]

Table 6: Observed and expected deaths from selected major causes (1957-1983) in TiO2 and TiCl4 cohorts. Expected numbers are based on Du Pont male wage mortality rates.

 

TiO2-exposed cohort

TiCl4-exposed cohort

Observed

Expected

90% acceptance range*

Observed

Expected

90% acceptance range*

All causes

194

175.5

154-198

87

81.5

67-97

All cancers

37

42.8

32-54

24

20.4

13-28

Cancer of the respiratory system

14

16.6

10-24

9

8.1

4-13

Lung cancer

9

15.3

9-22

7

7.5

3-12

Diseases of the respiratory system

11

8.3

4-13

3

3.3

0-7

*90% acceptance range is defined such that the probability under the null hypothesis of obtaining a number that exceeds the high end of the range or is less than the low end of the range is less than 0.05.

[Derived from on tables 6a and 6b of report.]

Table 7: Multiple logistic regression analyses of lung cancer deaths according to TiO2. TiCl4, PKT (pigmentary potassium titinate) and asbestos exposures

Occupational variables in model

Adjusted odds ratio (OR)

90% confidence limits on OR

lower

upper

Referent group

1.0

-

-

TiO2

0.5

0.2

1.1

TiCl4

1.7

0.7

4.0

PKT

0.0

-

-

asbestos

1.0

0.5

1.9

27 cases, 331 controls

[Based on table 7 of report.]

Table 8: Multiple logistic regression analyses of incident chronic respiratory disease according to TiO2. TiCl4, PKT (pigmentary potassium titinate) and asbestos exposures

Occupational variables in model

Adjusted odds ratio (OR)

90% confidence limits on OR

lower

upper

Referent group

1.0

-

-

TiO2

0.8

0.6

1.3

TiCl4

1.1

0.7

1.7

PKT

1.6

0.7

3.6

asbestos

1.6*

1.1

2.3

88 cases, 898 controls

*Said to be statistically significant at the 0.05 probability level

[Based on table 9 of report.]

Applicant's summary and conclusion

Conclusions:
This study found no clear, statistically significant association between exposure to titanium tetrachloride or titanium dioxide and the risk of developing lung cancer or respiratory disease.

It was argued in the report that the slightly elevated odds ratio for lung cancer associated with exposure to titanium tetrachloride should not be inferred to be a causal association since this finding was based on small numbers, showed a weak and statistically non-significant association with no clear dose-response trend, and was derived from data for which there was no adjustment for cigarette smoking.