Background, and aim of the study

1. ABSENCE OF ELEVATED FREQUENCY OF CHROMOSOMAL ABERRATIONS OF PERSONS EXPOSED TO LONG-TERM EFFECTS OF METHYLENE DIPHENYL DIISOCYANATE (MDI) Gy. Farkas, G. Szekely, S. Gundy National Institute of Oncology, Ráth Gy. u. 7-9., H-1122 Budapest, Hungary Background, and aim of the study MDI is a bifunctional electrophyl widely used in the industry for the production of polyurethane elastomers, coatings, adhesives, sealing materials, car accessories, etc. Since it is a highly reactive chemical that binds to DNA, therefore, is probably genotoxic. Some data report that MDI is positive in Ames test, causes elevated frequencies of micronuclei, SCEs, and DNA adducts. However, IARC concluded that there is inadequate evidence for mutagenicity and carcinogenicity of monomeric or polymeric MDI in human. Former exposure studies were obtained with uncertain methodologies, and studiedonly on very few persons with unknown exposure levels at workplaces. Recently the largest epidemiological studies (Sweden, England) reported that occupational exposure to diisocyanates did not cause an overall increased cancer risk, however, these exposures were not confined to MDI alone, only to iso-cyanates in general. This study examines chromosomal aberrations (CAs), of 296 persons who were exposed exclusively to MDI between 1992 and 2006, and were followed from the very beginning of the operation of the plant where the concentration of MDI was always kept under”permissible” levels (0.001-0.02 mg/m3.) Material and Methods Study subjects The cohort included 237 males and 59 females (mean age 36.5 9.8 years) exposed during polyurethan production to MDI, and, 184 males and 112 females (mean age 35.9 10.3 years) as controls, respectively. The CA data of subjects were compared to controls on one hand, and to their initial self-control data on the other hand. Follow up was available in some cases only less than 15 years (see: Table 3). Blood sampling, culturing and chromosome analysis For the analysis of chromosomal aberrations lymphocytes were cultured for 48-50 hrs, according to conventional methods.The analysis of structural aberrations included chromatid- and chromosome breaks, chromatid exchanges, and dicentric and ring chromosomes. Statistics CAs were statistically analysed by Wilcoxon test. Table 1. Spontaneous rate of chromosomal aberration in MDI exposed persons Results The aberrant cell frequencies of exposed group were compared with age-, sex-, and smoking habit-matched controls (Tables1, 2). The differences were not significant between genders or age groups within the exposed population (Table 1). However, the smokers revealed higher aberration frequency than non-smokers. Within the control group we found differences between genders, and smokers vs. non-smokers, but not in different age-categories (Table 2).If we compared CAs of controls tothat of exposed subjects, controls had significantly higher aberration rate than the exposed persons in each respect surprisingly. In order to assess whether the duration of exposure affects the CA frequency, self-control data of MDI-workers (0-1 year of exposure) were used to compare them to their data with prolonged exposures (Table 3). The frequency of any type of CAs was rather constant during the MDI exposure-period. Aberrant cells showed no significant elevation between initial self-control and exposure -data. Cancer cases (only description is here): 3 lung cancers, mamma and head and neck carcinoma were found in the cohort. Because of the small number of the cohort these data were statistically not evaluated. Significance: ap= 0.0277 b p= 0.0363 dp=0.006 g p<0.0001 Table 2. Spontaneous rate of chromosomal aberration in unexposed persons Chemical structure of MDI Significance:b p= 0.0363 c p=0.0005 dp=0.006 e p=0.0001 g p<0.0001 Table 3. Effect of the duration of MDI exposure on the chromosomal aberrations of the cohort Conclusions Absence of elevated frequency of chromosomal aberrations in this cohort exposed to MDI during 7-15 years provides convincing evidence that this compound has no mutagenic and genotoxic activity when working conditions are kept strictly safe. Our cytogenetic observations are among the first in the research of mutagenicity of exposure to MDI alone and not in a combination with other isocyanates. This study underlines the usefulness of the follow-up of CA analysis of workers. As it was seen, the controls had higher aberration frequencies than the exposed subjects. The phenomenon may be explained with the fact that the persons working in MDI plant are probably more careful in precautionary measures at the workplace and their life-styles than those unexposedoccupationally. Examination of cancer incidences should be followed in the future. Significance: p>0.05 in all aspects