Tetraammineplatinum dichloride

Sensitisation data (human)

Administrative data

Endpoint:

sensitisation data (humans)

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

01-Jan-1976 to 31-Dec-1995

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Not a guideline study, but data are scientifically acceptable in the context of an occupational cross-sectional study

Data source

Reference

Reference Type:

publication

Title:

20 Years of medical surveillance on exposure to allergenic and non-allergenic platinum compounds: the importance of chemical speciation

Author:

Linnett PJ & Hughes EG

Year:

1999

Bibliographic source:

Occupational and Environmental Medicine, 56, 191-196

Materials and methods

Type of sensitisation studied:

respiratory

Study type:

survey

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Longitudinal/cohort study
Analysis of 20 year data on exposure to soluble platinum compounds and medical surveillance results to confirm that tetraammine platinum dichloride is not allergenic.

GLP compliance:

no

Remarks:

GLP not applicable to this type of study

Test material

Test material information

Constituent 1

Reference substance name:

Tetraammine platinum dichloride

IUPAC Name:

Tetraammine platinum dichloride

Constituent 2

Reference substance name:

[(NH3)4Pt]Cl2

IUPAC Name:

[(NH3)4Pt]Cl2

Constituent 3

Reference substance name:

TPC

IUPAC Name:

TPC

Test material form:

other: Airborne [possibly particulate matter]

Method

Type of population:

occupational

Ethical approval:

not specified

Subjects:

Total number of persons in cohort from which data were generated: 547 (in 3 process areas); sub-group of chemical processs operators (CPOs; exposed to soluble platinum for at least 50% of their work) identified within each exposure group, total n=341

EXPOSURE DATA
- DURATION
New employees who started work between 01-Jan-1976 and 31-Dec-1995, followed up until 31-Dec-1995, were considered for inclusion the study. Criteria for inclusion:
- no previous exposure to soluble platinum compounds
- work gave regular exposure to soluble platinum compounds which required subjects to undergo medical surveillance
- employed for long enough to have at least one medical examination (these were performed every 3 months)

- CATEGORIES
3 exposure categories to airborne soluble platinum, including TPC:
- PGM refinery (n=406, CPOs=270); workers exposed to chloroplatinates, but not TPC; lowest Pt exposure of the 3 groups
- TPC lab (n=41; CPOs=31); workers regularly exposed to TPC and chloroplatinates; highest Pt exposure of the 3 groups
- Autocat (n=100; CPOs=40); exposure to TPC only; group with intermediate Pt exposure

SUBJECT DESCRIPTION
PGM refinery: total n=406; 373 men, 33 women; mean age 29 years (range 18-61); 199 smokers; 1 atopic
TPC lab: total n=41; 40 men, 1 woman; mean age 25 years (range 17-47); 11 smokers; 0 atopic
Autocat: total n=100; 85 men, 15 women; mean age 26 years (range 16-61); 33 smokers; 4 atopic

A sub-group of chemical processs operators (CPOs; exposed to soluble platinum for at least 50% of their work) was identified within each exposure group, with the following characteristics:
- PGM refinery: total n=270; 257 men, 13 women; mean age 30 years (range 18-59); 164 smokers; 0 atopic;
- TPC lab: total n=31; 31 men, 0 women; mean age 25 years (range 17-47); 9 smokers; 0 atopic;
- Autocat: total n=40; 40 men, 0 women; mean age 29 years (range 16-61); 17 smokers; 0 atopic

MEDICAL SURVEILLANCE ROUTINE
Enquiry about symptoms and skin prick tests every 3 months with 3 platinum salts (ammonium hexachloroplatinate up to 1994, sodium hexachloroplatinate throughout, sodium tetrachloroplatinate up to 1992, TPC from 1992 onwards) at 10 mg/ml in glycerol carbol saline or 0.9% saline; spirometry every 6 months. Positive responses (> or = to 2 mm dimaeter weal) were followed up with further testing.

SUBJECT TRANSFERS
11 employees (8 CPOs) from the PMG refinery transferred to the Autocat; 1 CPO from the TPC group and 1 from the Autocat transferred to the PGM refinery. Subjects who transferred between operations were considered to have withdrawn at the date of transfer and were not included in the analysis for the operation to which they transferred.

Clinical history:

Pre-employment medical examination; no atopic subjects employed in production jobs; 5 in office jobs in the original cohort.

Controls:

No control groups were included; comparisons were made between the 3 exposure groups.

Route of administration:

inhalation

Details on study design:

Occupational exposure was to TPC and/or chloroplatinates (depending on exposure group). Incidences of sensitisation within the first 5 years (60 months) of employment were evaluated in relation to exposure categories, in both the full cohort (547) and the subset of workers exposed to airborne soluble platinumfor at least 50% of their work 341). TPC/chloroplatinate exposures could not be measured separately when both substance types were airborne.

Results and discussion

Results of examinations:

FULL COHORT
PGM refinery (lowest exposure to airborne soluble platinum, exposure to chloroplatinates only, i.e. not TPC): 110/406 cases of sensitisation (27%); 106/270 cases (39%) in the CPO sub-group

TPC lab (highest exposure to airborne soluble platinum, exposure to TPC and chloroplatinates): 5/41 cases of sensitistation (12%); 5/31 cases (16%) in the CPO sub-group; probability of sensitisation was significantly less than in the PMG refinery (p<0.05), relative risk (with 95% confidence interval) reported as 0.33 (0.14-0.78).

Autocat (intermediate exposure to airborne soluble platinum, exposure to TPC only): 0/100 cases of sensitisation (0%); 0/40 cases (0%) in the CPO sub-group; probability of sensitisation was significantly less than in the PMG refinery (p<0.001) and the TPC lab (p<0.05), relative risk 0.00

CPO SUB-GROUP
PGM refinery, no relationship between probability of sensitisation and age at the start of employment; strong evidence of a relationship with smoking; smoking-adjusted RRs (with 95% CI) for the TPC lab and the Autocat groups, compared with the PGM refinery group, were 0.47 (0.20-1.12; not statistically signficant) and 0.00 (p<0.001)

PGM refinery(lowest exposure to airborne soluble platinum, exposure to chloroplatinates only, i.e. not TPC): median time to diagnosis of sensitisation 13 months (range 1-108 months); 80/106 cases diagnosed in first 2 years of employment; 1.4 cases/100 person-months in the first 5 years of employment

TPC lab (highest exposure to airborne soluble platinum, exposure to TPC and chloroplatinates): median time to diagnosis of sensitisation 37 months (range 7-52 months); 0.5 cases/100 person-months in the first 5 years of employment

Autocat (intermediate exposure to airborne soluble platinum, exposure to TPC only): no cases of sensitisation in CPO sub-group or this group in the original cohort

Sensitisation incidence calculations were restricted to first 60 months of employment to prevent long-term "survivor" bias.

Any other information on results incl. tables

"Supports the original study [Cleare MJ et al., 1976. Clin Allergy, 6, 183], which showed a lack of response to TPC in subjects who were sensitive to chloroplatinates."

Applicant's summary and conclusion

Conclusions:

Tetraammine platinum dichloride showed a lack of allergenic potential in an occupational study involving 547 workers exposed to airborne TPC, chloroplatinates or a combination thereof (341 of whom were exposed to soluble platinum for at least 50% of their work).

Executive summary:

This longitudinal cohort was designed to investigate the allergenic potential of tetraammine platinum dichloride (TPC) in groups of workers exposed airborne concentrations of this and/or chloroplatinate salts. Of 341 chemical process operators exposed to soluble airborne platinum for at least 50% of their work, those with lowest exposure to total platinum (no TPC exposure) exhibited 1.4 cases of sensitisation/100 person months in the first 5 years of employment; those with the highest exposure to total platinum (a combination of TPC and chloroplatinates) exhibited 0.5 cases/100 person-months; none of those exposed to TPC alone (intermediate total Pt exposure) displayed any indications of sensitisation. Smoking-adjusted relative risk for intermediate TPC exposure vs. no TPC exposure was 0.00 (p<0.001). The authors concluded that this study "confirms the allergenic potential of the complex halogenated salts of platinum and shows the lack of effect attributable to TPC alone"; and that "the soluble platinum compound TPC is not allergenic under normal industrial conditions".