Registration Dossier

Administrative data

Endpoint:
health surveillance data
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Blood cadmium as an indicator of dose in a long-term follow-up of workers previously exposed to cadmium
Author:
Järup L, Persson B and Elinder C
Year:
1997
Bibliographic source:
Scand. J. Work Environ. Health 23:31-36

Materials and methods

Study type:
biological exposure monitoring
Endpoint addressed:
repeated dose toxicity: inhalation
Principles of method if other than guideline:
An investigation was carried out to follow up the tubular function of 46 workers initially examined in 1984 and heavily exposed to cadmium from 1955 to 1978 and the occurence of renal stones among these workers. Three different markers of tubular dysfunction were also studied, and blood cadmium was evaluated as an estimate of dose after the cessation of cadmium exposure.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Cadmium


Method

Type of population:
occupational
Ethical approval:
not specified
Details on study design:
Subjects:
- Number of participants: 46 solderers (44 men and 2 women)
Exposure Measurements:
- Exposure duration: 1955 to 1978
- Air concentrations: 10 to 2000 µg/m3 (in 1976)
- Average air cadmium concentrations: Low: 50 µg/m3; Medium: 150 µg/m3 and High: 500 µg/m3.
Individual cumulative exposure estimates were computed by multiplying the air concentrations by the number of years spent at each exposure level.
Sample collection:
- Morning urine samples were collected in polyethylene bottles (4 g of sodium bicarbonate was administered the night before, to prevent degradation of β2-microglobulin).
Kidney-function measurements
- Parameters analysed and method used:
Urinary excretion of β2-microglobulin (U-β2-microglobulin) - radio immunoassay;
Protein HC (α1-microglobulin) - zone immunoelectrophoresis assay (Holmqvist et al., 1993);
Urinary N-Acetyl-β-D-glucosaminidase (U-NAG) - fluorometric method (Yueli et al., 1982);
Cadmium in blood (B-Cd) and urine (U-Cd) - atomic absorption spectrophotometry (Lagesson and Andrasko, 1979).
All urinary measures were adjusted to creatinine.
Cut off levels:
- U-β2-microglobulin: 95th percentile (34 µg/mmol creatinine) in a standard reference population.
- U-NAG: 0.5 U/mmol creatinine
- HC (α1-microglobulin): 1.0 mg/mmol creatinine

Results and discussion

Results:
- Comparison between the individual urinary excretion of β2-microglobulin in 1984 and 1993: 40% of the workers showed irreversible signs of tubular dysfunction both in 1984 and in 1993.
- Comparison between the urinary excretion of cadmium (U-Cd) in 1984 and 1993: Lower mean U-Cd (by 57 %) was observed in 1993 (3.7 nmol/mmol creatinine) than in 1984 (8.6 nmol/mmol creatinine) (See figure 4).
- Urinary excretion decreased from 4.2 to 2.2 nmol/mmol creatinine (48%), among the subjects with a normal tubular function (<0.1% decreased tubular reabsorption), whereas for those with slight (0.1% - < 2.5%) or pronounced (≥ 2.5%) tubular dysfunction, the mean decrease was from 9.1 to 4.0 (56%) and from 18.5 to 7.1 nmol/mmol creatinine (62%), respectively was observed.
- Biological half-times for U-Cd: Graphically estimated to be 9.5, 8.0 and 7.2 years, respectively.
- Urinary excretion of tubular markers in relation to current (1993) blood-cadmium (B-Cd) and urinary-cadmium (U-Cd) levels as dose variable:
(a) Dose dependent increase of urinary excretion of β2-microglobulin, protein HC (α1-microglobulin) and NAG were observed. Elevated dose response curve (adjusted to age, i.e., 55 years) was observed for HC (α1-microglobulin) than that of β2-microglobulin. (See figure 2 and table 1)
(b) Elevated urinary excretion of β2-microglobulin, protein HC (α1-microglobulin) and NAG were observed. U-Cd was a less useful indicator of dose in this long-term follow-up (See table 2).
- The prevalence of β2-microglobulinuria remained unchanged, (See figure 4). The dose-response curve from 1993 moved to the left, when compared with the one based on data from 1984 (See figure 3).
- Occurrence of renal stones in 46 cadmium-exposed solderers in relation to the current (1993) levels of cadmium in blood (B-Cd): History of renal stones was significantly more common for workers with higher B-Cd level. (See table 3)

Any other information on results incl. tables

- Significant associations were found between the cumulative air cadmium levels and all the parameters used to indicate tubular proteinuria.

- Significant associations were found with current U-Cd or current B-Cd when used as dose estimates.

All the tables and figures are attached in an MS word document in background material.

Applicant's summary and conclusion

Conclusions:
Cadmium induced tubular dysfunction is irreversible and best assessed by an analysis of protein HC (α1-microglobulin) in urine. B-Cd is the best dose estimate several years after the cessation of exposure, whereas U-Cd is less suitable for dose assessment in follow-up studies of persons with persistent tubular damage.
Executive summary:

An investigation was carried out to follow up the tubular function of 46 workers (initially examined in 1984 and heavily exposed to cadmium from 1955 to 1978) and the occurrence of renal stones among these workers. Three different markers of tubular dysfunction were also studied and blood cadmium was evaluated as an estimate of dose after the cessation of cadmium exposure.

Cadmium in blood (B-Cd) and urine (U-Cd) and the urinary excretion of β2-microglobulin (U-β2- microglobulin), protein HC (α1-microglobulin) and N-Acetyl-β-D-glucosaminidase (N AG) were determined.

Although cadmium exposure ceased in 1978, 40% of the workers showed signs of tubular dysfunction both in 1984 and in 1993. The current B-Cd was the best dose indicator of cadmium. Dose-response relationships were found for Cd-B and various tubular markers (U-β2-microglobulin, protein HC and NAG). Elevated dose response curve (adjusted to age, i.e., 55 years) was observed for HC (α1-microglobulin) than that of β2-microglobulin. The levels of Cd-U had an average decrease of 48% for persons with a normal tubular function, 56% for those with slight tubular dysfunction, and 62% for workers with severe tubular damage. A history of renal stones was significantly more common for workers with high B-Cd levels.

Hence, cadmium induced tubular dysfunction is irreversible and best assessed by an analysis of protein HC (α1,-microglobulin) in urine. B-Cd is the best dose estimate several years after the cessation of exposure, whereas U-Cd is less suitable for dose assessment in follow-up studies of persons with persistent tubular damage.