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Toxicological information

Epidemiological data

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Administrative data

epidemiological data
Type of information:
experimental study
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study report with less than complete details.

Data source

Reference Type:
study report

Materials and methods

Study type:
cohort study (retrospective)
Endpoint addressed:
genetic toxicity
Test guideline
no guideline followed
Principles of method if other than guideline:
Between years 1989 and 2008, 578 chromosome aberration analyses and cancer incidence were examined in 376 employees of
MDI-producing-factory, immediately and after entering the plant during different exposure-periods. SCE analyses were
carried out on 78 persons, and bleomycin sensitivity assay was studied on 124 persons. Age-, sex-, and smoking habit-matched unexposed
persons served as a reference group during the whole study. Self-control analyses were also applied in 76 cases with repeated CA examinations.
The follow-up for cancer incidence was defined as the time from the date of the first cytogenetic test until the date of cancer diagnosis.
GLP compliance:
not specified

Test material

Constituent 1
Reference substance name:
Cas Number:
Details on test material:
Exposures as experiences in PMDI production.


Type of population:
Ethical approval:
confirmed, but no further information available
Details on study design:
The chromosome study involved 578 examinations on 376 persons working in MDI factory between 1989 and 2008.
The corresponding age-, smoking- and sexmatched control group comprised also 376 persons free of known malignancies,
who attended for pre-employment medical examinations, routine laboratory tests or blood donation at various outpatient clinics in Budapest and
Northern Hungary, and had never been exposed to isocyanates or to known mutagens. The criteria for inclusion of subjects in the cohorts were:
(1) they had valid demographic data and were at least 18 years of age and without a previous cancer diagnosis at time of the cytogenetic test,
(2) the cytogenetic analysis was based on a minimum of 100 metaphases.

Two computer files for the workers and controls were used as follows: one file with one record per individual including data on follow-up, and
one file with one record per test including the results of CA analyses, SCE- and bleomycin test data as well as data on smoking and occupational
exposures, and the date of the occurrence of cancer. Demographic characteristics of persons are presented in Table 1. In a total 578
CA analyses were carried out during the 19-year period, out of which 376 persons had at least one examination.

Out of 376 persons 78 were examined for SCE frequencies exposed to MDI at least 2 years, but no longer than 5 years, and 124 persons were
studied for bleomycin sensitivity assay exposed at least 2 years to MDI, respectively. Controls were matched for age, sex, and smoking habits in
the same amount of analyses, and during the same period as the index persons were investigated.

Self-controls for the follow-up of CAs were available for 76 subjects, but all together 84 CA analyses were done, because in some cases 2-4
repeated cytogenetic analyses were conducted in this group. represents separately the distribution of the number of examinations according to
the duration of exposure-period, and the Table 3 demonstrates the number of persons participating in different exposure-periods, following their
self-control analyses.
The whole study group of 376 persons was followed for cancer incidence with the registration of person-time, i. e. the follow-up period was defined as the time from the date of the first cytogenetic test until the date of cancer diagnosis. Information on cancer incidence was obtained through
linkage with the national cancer registry between 1990 January and 2009 May, and an active system of follow-up for morbidity or mortality via
contacts with local occupational physician and local (county-) cancer registry was also conducted during this period. The same method was applied
for the referent group, either.

Exposure assessment:
Details on exposure:
Exposure situations
Period for employment for MDI-exposed workers ranged between 0-19 years. Annual concentrations of MDI ranged between
0.0011-0.02 mg/m3 during this period. Exposures other than MDI and smoking were also taken into consideration, and thus, 32 persons
were exluded from this study due to other occupational exposures. Their data-analysis will be published elsewhere. Information on smoking status
at the time of first test was available, and according to this 35% of workers were smokers. More detailed information on
smoking was available only for a small proportion of subjects, therefore, this information was not used.
Statistical methods:
The normal distribution of all examined groups was investigated according to the Kolgomorov–Smirnov test. CAs were statistically analysed by the
Wilcoxon test. The influence of age and smoking on CAs was tested by a multiple regression method. The associations between mutagen sensitivity, and rates of CAs were estimated by odds ratios (ORs) with 95% confidence intervals. In order to calculate the ORs we compared the highest quartile
of subjects with the lowest one. All P values were determined on the basis of two-sided t tests and P <0.05 was considered as the limit of significance. All analyses were performed using the GraphPad Instat (v. 3.05, 2000) and GraphPad Prism (v. 3.02, 2000) computer programs
(GraphPad Software, Inc. .

Results and discussion

Chromosome analysis: The frequencies of aberrant cells did not differ significantly from those of controls when the both sexes were examined.
Analysis of the spectrum of scored structural CAs showed also no elevated frequencies for chromatid-, and chromosome type
aberrations in lymphocytes for males and females.

Sister Chromatid Exchange: Out of 376 MDI-exposed persons we examined 78 subjects for SCEs as well. In a total they had significantly higher SCE levels than the matched referent group. On the other hand because of small difference of SCEs between exposed and controls (the minimum and maximum range of SCE in cells was almost equal in either group, and no cells with extremely high SCE frequencies were found), it might make it difficult to define a high SCE level associated with MDI exposure or its role even in cancer risk prediction. Furthermore, based on the conclusion of different reviews CAs but not SCE were predictive of cancer, with more confidence SCEs represent probably tolerable biological variations and/or reversible biological changes, whereas CAs, particularly their certain types may represent irreversible biological alterations that can lead to the development of

Applicant's summary and conclusion