Statistics from Altmetric.com
In their paper updating a previous investigation of the mortality of workers employed at a factory producing chemicals in North Wales, Sorahan, Hamilton, and Jackson plead for priority to be given for studies on the cancer experience of other working populations exposed to N-phenyl-β-naphthylamine (PBN).1
It is, therefore, disappointing that the authors made no reference at all to studies conducted by the British Rubber Manufacturers' Association (BRMA), and others, on rubber workers employed after 1950. These workers would have been exposed to PBN, and to other antioxidants still in use after the discontinuance (in 1949) of Nonox “S” and similar compounds contaminated by β-naphthylamine (BNA). This contaminant, a potent human bladder carcinogen, was at a concentration (2500 ppm) sufficient to double the incidence of bladder cancer in those exposed.
A particular study2 which singled out a large cohort of male rubber workers (2577) at a tyre factory, who experienced mixed exposure, but also exposure to PBN as the predominant antioxidant was followed up from 1951 to 1990. No excess of bladder tumours was found (25 observed, 24.1 expected; standardised incidence ratio (SIR) 104, 95% confidence interval (95% CI) 67 to 153). A negative result in such a mixed exposure situation, where exposure can be confirmed in occupational hygiene terms, strongly suggests that whatever agents are being used they are not (under those conditions of manufacture) exerting a carcinogenic influence. Also a subcohort of 1322 men at the same factory, but employed before the end of 1949, who could be excluded from concomitant exposure to Nonox “S”, but who worked on the PBN flowline, gave similar results (12 observed, 14.5 expected; SIR 83, 95% CI 43 to 145).
The rubber industry deserves to be reassured from such purposefully conducted studies as soon as possible.
There is no evidence that PBN is itself carcinogenic. As the authors indicate, it is not a proved animal carcinogen and it is not mutagenic to bacteria. If some dephenylation occurs in vivo, it probably does so to a very minor degree, and at a stage in the metabolic cycle that renders any metabolites relatively innocuous, or unavailable to the urothelium.2
It is one thing to cast suspicion of carcinogenicity at manufacturing industry, quite another to transcribe this into the situation of open usage; I cite the auramine and magenta example in the dye industry. From the data shown in their figure, Sorahan et al essentially rely on only six cases of bladder tumour in a subcohort of 94 men, all allegedly exposed to PBN, but 52 of whom had mixed exposure to o-toluidine and to 2-mercaptobenzothiazole (MBT) as well. Three tumours related to this mixed exposure group, three to the 42 men allegedly exposed only to PBN.
The authors have undoubtedly shown that an excess of bladder tumours has occurred in the factory workforce studied, but on all the evidence presented, in my opinion, it is unjustifiable to ascribe a suspicion of carcinogenicity to PBN, when overall the epidemiological and other evidence available is more reassuring than not.
Sorahan and Jackson reply—We agree with Veys that his study of workers exposed to phenyl-β-naphthylamine (PBN) while engaged in the manufacture of rubber tyres indicates that such workers do not experience increased risks of bladder cancer,1-1 and that the findings of his study need to be considered along with our own new findings1-2 in arriving at any overall evaluation. Our simplest interpretation of the new findings was that “PBN (or a chemical reagent of chemical intermediate associated with the production of PBN at this factory in the 1930s or 1940s was a bladder carcinogen”, that other interpretations were possible and that all needed to be “treated with caution”. Our emphasis on the possible role of chemical intermediates matches the concerns of Veys—namely that epidemiological findings relating to workers engaged in the manufacture of a given chemical may be quite different to those pertaining to workers using the same chemical. Clearly, large scale studies relating to both sets of circumstances should assist confident interpretation.