Lead 2,4,6-trinitro-m-phenylene dioxide

Epidemiological data

Administrative data

Endpoint:

epidemiological data

Type of information:

other: Epidemiological Study (Occupational)

Adequacy of study:

key study

Study period:

1940-1965

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The rationale for the reliability scoring is based upon a Lead Study Quality Assessment tool for Carcinogenicity in both the Occupational Setting and the General Population developed by the Scientific Advisory Panel assembled to provide independent academic review of the Voluntary Risk Assessment for Lead. The Occupational and General Population Assessment assessed study quality on the basis of the following major aspects of study design, data collection and analysis. Adequacy of Cohort Definition Nature and Extent of Lead Exposure Indices Examiner Training and Procedures for Data Collection and Analysis Precision of Endpoint Definition Extent of Correction for Major Confounding Variables

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1992

Materials and methods

Study type:

cohort study (retrospective)

Endpoint addressed:

carcinogenicity

Principles of method if other than guideline:

Retrospective Cohort Study

Test material

Test material information

Constituent 1

Reference substance name:

Lead

EC Number:

231-100-4

EC Name:

Lead

Cas Number:

7439-92-1

Method

Type of population:

occupational

Ethical approval:

not applicable

Details on study design:

HYPOTHESIS TESTED (if cohort or case control study): This study is an extension of the follow-up of the US lead smelter cohort previously studied by Selevan et al from 1977 through 1988. The a priori outcomes of principal interest were malignant and nonmalignant renal disease and cerebrovascular disease.


METHOD OF DATA COLLECTION
- Type: Interview / Questionnaire / Record review / Work history / Clinical tests / other:
- Details: Death Certificates


STUDY PERIOD: 1940-1965


SETTING: Lead Smelter


STUDY POPULATION
- Total population (Total no. of persons in cohort from which the subjects were drawn): 1990 male hourly smelter workers
- Selection criteria: Worked ina a lead-exposed department for at least 1 year, with at least 1 day of employment at the smelter between 1940 and 1965.
- Total number of subjects participating in study: 1028
- Sex/age/race: Race was not available from personnel records for most cohort members, who were assumed to be white, This assumptions proved justified based on data from death certificates (982 of 985 decedents who had death certificates were White).
- Smoker/nonsmoker: No smoking data were availble for the cohort.
- Total number of subjects at end of study: 1028
- Matching criteria:
- Other:


COMPARISON POPULATION The US population was used as the referent group.
- Type: State registry / Regional registry / National registry / Control or reference group / Other comparison group:
- Details:


HEALTH EFFECTS STUDIED
- Disease(s):
- ICD No.:
- Year of ICD revision:
- Diagnostic procedure:
- Other health effects:


OTHER DESCRIPTIVE INFORMATION ABOUT STUDY:

Exposure assessment:

estimated

Details on exposure:

TYPE OF EXPOSURE: Occupational lead exposure from different departments in a lead smelter.


TYPE OF EXPOSURE MEASUREMENT: Area air sampling / Personal sampling / Exposure pads / Biomonitoring (urine) / Biomonitoring blood / other:
Average airborne lead concentrations based on 203 personal 8-hour samples.

EXPOSURE LEVELS: This cohort was heavily exposed to lead. A 1975 NIOSH industrial hygiene survey showed average airborned lead concentrations of 3.1 mg/m3, based on 203 personal 8-hour samples. However, in the study there was a High exposure group and a high lead/low other exposure group (See Delineation of Exposure Groups).


EXPOSURE PERIOD: 1940-1965 with at least one year of employment at the smelter.


POSTEXPOSURE PERIOD:


DESCRIPTION / DELINEATION OF EXPOSURE GROUPS / CATEGORIES: High lead exposure group had air lead levels in excess of 200 ug/m3 or 50% of jobs in area exceeded 2X standard. High lead/low other exposure groups included workers both exposed to high lead but 50% of jobs examined were exposed to airborne Cd, Zn, or As at levels above the current standards.

Statistical methods:

Cohort analysis was conducted via traditional life table methods using the Life Table Analysis System of the national Institue for Occupational Safety and health. The US population was used as the referent group. Significance testing and confidence intervals for standardized mortality ratios were calculated under the assumption that observed deaths were distributed as Poisson variables. A test for trend in standardized mortality ratios described by Breslow et al (1983) was used. Person-years at risk for cohort members began after they had completed 1 year of exposure but not earlier than 1940. In addition to underlying cause of death analysis, multiple cause of death rates for the US population from 1960 onwards were used for a comparison of the prevalence of nonmalignant renal disease on the death certificate in the cohort vs the referent population

Results and discussion

Results:

The original study had found elevated but nonsignificant risks for kidney cancer, stroke, and nonmalignant risks for kidney cancer, stroke, and nonmalignant renal disease, probably attributable to lead exposure. Deaths from accidents and nonmalignant respiratory disease were significantly elevated, but probably not as a result of lead exposure. In the updated study, no new deaths from nonmalignant renal disease occurred (9 observed, standardized mortality ratio of 1.21). Three more deaths from kidney cancer were observed, yielding a standardized mortality ratio of 1.93 (9 observed, 95% CI= 0.88, 3.67), which increased for those who had worked in areas with the highest lead exposure (8 observed, standardized mortality ratio = 2.39, 95% CI=1.03,4.71). Cerebrovascular disease remained elevated for those with more than 20 years of exposure (26 observed, standardized mortality ratio = 1.46, 95% CI=0.92, 2.07).

Confounding factors:

Other contaminants in the workplace including but not limited to Cd, Zn, As and silica. No smoking histories or dietary habits were obtained.

Strengths and weaknesses:

The study lacked detailed data on lead exposures, detailed data on potential confounding exposures to cadmium and arsenic, and smoking data. However, the authors did have data indicating that this cohort was exposed to high levels of lead and that exposures to cadmium and arsenic were generally minor. Furthermore, many of the outcomes of a priori interest are not related to smoking.

Any other information on results incl. tables

Significant mortality results for selected causes by duration of exposure for entire cohort

Cause (ICD-9 Code)	1 -5 years-SMR	5 -20 years-SMR
Stomach Cancer (151)	2.41*
Nonmalignant respiratory disease	1.43*	1.45*
Emphysema (492)	2.69*
Pneumoconioses and other respiratory (470 -478, 494 -519)	1.93*	2.38*
Transportation accidents (E800 -E848, 929.0 -929.1)	2.08*
Other accidents (E890 -E928, E929.4 -E929.9)	2.68*
All deaths	1.14*

*Significantly elevated at the .05 level (two-tailed).

The previously observed excess deaths due to accidents and nonmalignant respiratory disease continued to be significantly elevated in this cohort. However, a review of death certificates and employment applications indicated that these excesses were probably due to work in the mining industry rather than lead exposure.

Lung cancer and bladder cancer deaths showed nonsignificant elevations (standardized mortality ratios = 1.18 and 1.93, respectively). However, neither cancer was particularly elevated in the subcohort with high lead exposure. Neither cancer has been implicated in animals studies, and, with the exception of a single study with a lung cancer excess, there is little epidemiologic evidence implicating these cancers. Both cancers are related to smoking, and excess smoking in the cohort may have contributed to their elevation.

Regarding a priori outcomes, the most important findings from this update are the persistence of kidney cancer excess and the lowering of the nonmalignant renal disease excess. Cerebrovascular disease mortality was elevated only slightly overall. However, there was an increasing trend in standardized mortality ratios with increasing duration of exposure (P = .07).

The kidney cancer excess (standardized mortality ratio = 1.93), while based on small numbers (nine observed), is supported by the increase in the standardized mortality ratio in the subcohort with high lead exposre (standardized mortality ratio = 2.39). The kidney cancer excess was not clearly related to duration of exposure, but duration of exposure fails to account for intensity; thus, duration may not be a good indication of cumulative dose. The fact that animal studies show that lead causes kidney cancer lends strength to these findings. Kidney cancer is only weakly related to smoking, and excess smoking by this cohort would not be expected to lead to an appreciable excess.

That a kidney cancer excess was not observed in other studies may be partly attributable to a lack of power in those studies due to small sample size. On the other hand, the study by Cooper et al (1985) did have high exposure and substantial sample size, yet the kidney cancer standardized mortality ratio was only 0.50 (10 observed). There is no obvious explanation for this discrepancy with these findings.

The excess of nonmalignant renal disease observed in this data was concentrated in earlier calendar periods and among those with logest duration. Studies of other lead cohorts have also found that nonmalignant renal disease excesses were confined to earlier calendar periods, among those exposed to presumably high historical levels.

Applicant's summary and conclusion

Conclusions:

This cohort with high lead exposure showed a diminishing excess of death from nonmalignant renal disease, a continued excess from kidney cancer, and an excess of cerebrovascular disease only in those with longest exposure to lead.

Executive summary:

Objective: Mortality studies of lead workers have shown excesses of nonmalignant renal disease and cerebrovascular disease. Animal studies and one human study have shown excess of kidney cancer. This is an updated mortality study of male lead smelter workers (n = 1990).

Methods: An analysis was conducted using standard life table techniques. The updated analysis added 11 years of follow-up and 363 new deaths.

Results: The original study had found elevated but nonsignificant risks for kidney cancer, stroke, and nonmalignant renal disease, probably attributable to lead exposure. Deaths from accidents and nonmalignant respiratory disease were significantly elevated, but probably not as a result of lead exposure. In the updated study, no new deaths from nonmalignant renal disease occurred (9 observed, standardized mortality ratio = 1.21). Three more deaths from kidney cancer were observed, yielding a standardized mortality ratio of 1.93 ( 9 observed, 95% CI = 0.88, 3.67), which increased for those who had worked in areas with the highest lead exposure ( 8 observed, standardized mortality ratio = 2.39, 95% CI = 1.03, 4.71). Cerebrovascular disease remained elevated for those with more than 20 years of exposure (26 observed, standardized mortality ratio = 1.41, 95% CI = 0.92, 2.07)..

Conclusions: This cohort with high lead exposure showed a diminishing excess of death from nonmalignant renal disease, a continued excess of cerebrovascular disease only in those with longest exposure to lead (Am J Public Health. 1992;82: 1641 -1644).