Development of an exposure assessment for the risk of bladder cancer from aromatic amines and evaluation of the effect of bladder cancer disease on employment

Status:

completed 11/2021

Aims:

The aim of the scientific project is to achieve a consensus in collaboration between occupational physicians and urologists, in which an orientation dose for carcinogenic aromatic amines is recommended, which can be assessed as relevant or causal for the development of job-related urothelial tumors.

Exposure to aromatic amines is ubiquitous. Therefore, in cases of suspected occupational disease 1301 (BK 1301), evidence of exposure alone cannot prove that urinary bladder cancer (BC) is substantially caused by occupational influences. Therefore, it was attempted to derive an indicative threshold dose for carcinogenic aromatic amines from epidemiological or animal studies or by read-across from smoking as exposure, which could be relevant for the development of occupationally induced urinary bladder tumours in the context of the expert opinion. Furthermore, a consensus of occupational physicians and urologists for the assessment of the exposure to carcinogenic aromatic amines in cases of suspected cases of BK 1301 defined as objective to enable a more standardized and thus fairer assessment of all affected insured persons. The framework conditions for assessing the reduction in earning capacity (MdE) for BK 1301 and BK 1321 were reviewed.

Activities/Methods:

A systematic literature search in the databases PubMed, Web of Science and Scopus, via cross-references and hand searching was performed according to PRISMA-P checklist, with definition of a PICO term, and registration on the PROSPERO server. The results as well as further approaches for exposure estimation and risk assessment of carcinogenic aromatic amines at BK 1301 were presented and discussed at a workshop. Subsequently, a working group of experts experienced in the assessment of occupational bladder carcinomas and statisticians developed the BK 1301 matrix as a convention for the assessment and evaluation of the causal relationship in urinary bladder carcinomas after relevant occupational exposure to carcinogenic aromatic amines based on the results of a workshop with more than 230 participants.

Results:

The abstracts of 613 articles were reviewed independently by two researchers and assessed with respect to predefined inclusion and exclusion criteria. After exclusion of 490 articles, 123 considered relevant papers were read as full texts. Due to insufficient study design and missing information on exposure, 108 studies were excluded. A doubling dose for urinary bladder cancer risk was derived for o-toluidine from data of two studies, which were based on the same study population. However, several limitations exist concerning the attribution of risk to inhalational exposure, such as additional dermal exposure and possible contamination of the chemicals with 4-aminobiphenyl. For other aromatic amines, in particular 2-naphthylamine and 4-aminobiphenyl, this approach was not possible due to lack of data in human studies. The derivation of a doubling dose of carcinogenic aromatic amines from 12 animal studies did not appear to be feasible due to the partly very small number of test animals, very heterogeneous methodology, and thus difficult to compare exposure conditions. There is one study with derivation of a cumulative dose of carcinogenic aromatic amines relevant for urinary bladder carcinoma by analogy to tobacco smoking, which, however, also has some limitations such as the attribution of the total urinary bladder carcinogenic potency of tobacco smoke to the three K1 substances 4-aminobiphenyl, 2-naphthylamine and o-toluidine.

At an online workshop, different approaches to exposure estimation and exposure assessment of urinary bladder cancer risk from aromatic amines were presented and discussed. Due to the lack of valid exposure data for carcinogenic aromatic amines, a working group subsequently derived a BK 1301 matrix as a convention for exposure assessment in urinary bladder carcinomas after relevant occupational exposure to carcinogenic aromatic amines based on all the approaches presented (including epidemiological data and comparison with the risk associated with smoking), which can also be applied if individual cumulative exposure data are lacking. It can be used to evaluate occupational indicators such as exposure duration, exposure frequency and exposure intensity, but also the age of onset, the latency period and smoking behaviour with regard to recognition of urinary bladder carcinoma as BK 1301.

Publications are available on the estimation of the MdE in the case of recognized BK 1301. These publications are still valid today and can also be applied to the BK 1321. The MdE consists of the basic MdE for the mental stress and impairment caused by the tumour disease on the one hand (to be assessed by occupational medicine on the basis of the tumour stage) and the organic functional disorders of the therapy and tumour sequelae on the other hand (to be assessed by urology).

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