Cancer risk assessment for workers exposed to nitrosamines in a warehouse of finished rubber products in the Eastern Townships (Québec, Canada)

This risk assessment was undertaken at the request of Dr. Louise Soulière, director of public health and evaluation at the Agence de la santé et des services sociaux de l'Estrie.

The objective of this work is to assess whether workers in a warehouse of finished rubber products in the Eastern Townships are at risk of contracting cancer because of the presence of nitrosamines in the workplace ambient air and, in the case of a non-zero risk, to suggest a threshold limit not to be exceeded in order to make the risk negligible.

The methodology used involves estimating workers' exposure to nitrosamines in the warehouse; assessing the carcinogenic potential for humans of the main nitrosamine molecules found in that environment; estimating the dose-cancer excess relationship based on epidemiological studies published so far and estimating the cancer risk associated with such exposure. This will allow suggesting an occupational exposure limit aimed at preventing the type of cancers potentially attributable to such exposure.

Between 2005 and 2008, concentrations of total nitrosamines in various areas of the warehouse ranged from 0.74 to 11.43 μg/m³ with arithmetic means of 2.89 to 4.59 μg/m³, depending on the work stations or the targeted sites. Half of those concentrations were lower than 3.53 μg/m³, with an overall arithmetic mean of 3.95 μg/m³. Concentrations of N-nitrosodimethylamine (NDMA) represent about 80% of total nitrosamines. These levels are similar to those observed elsewhere in the world.

Research shows that many nitrosamines found in the work environment, including NDMA, are carcinogenic in animals. Carcinogenic effects were observed for oral and respiratory exposures. The type of cancer induced depends on the route of entrance. The incidence of cancer is based on the daily administration dose and duration of exposure.

The cancers would be initiated by some metabolites of nitrosamines activated by an oxidative mechanism, which have the power to produce mutations in DNA. Human cells metabolize nitrosamines in a manner similar to that of animal cells and nitrosamine metabolites produced in rodents are also produced in humans. It has been shown that several human tissues (liver, kidney, lung and brain) metabolize NDMA and that the same DNA-adducts as those observed in experimental animal studies are also detected in humans. Based on these observations, it is reasonable to anticipate that NDMA and other nitrosamines present in these workplaces are carcinogenic in humans.

In 1998, experts commissioned by the International Agency for Research on Cancer (IARC) indicated that in the rubber products industry, there was a sufficient degree of evidence of a causal relationship to be inferred for excess mortality from certain cancers observed in some cohorts of rubber workers. However, the lack of measured concentrations of contaminants in the workplace prevents drawing up a causal link with specific risk factors.

Furthermore, confounding factors potentially associated with the cancer types observed were only rarely controlled in these studies. A meta-analysis by Kogevinas et al. reached the same conclusion.

In 1990 in Germany, a significant epidemiological investigation was initiated to explore the cancer risk factors associated with this industry. This investigation led to the publication of five articles between 1996 and 2000, on the follow-up of a cohort of some 11,000 workers employed between 1910 and 1991 in five different facilities manufacturing various rubber products such as tires and gaskets used in automobiles and appliances.

Based on our analysis of these studies, we found that the threshold inducing an excess risk of mortality from cancers associated with exposure to nitrosamines for an average exposure period of approximately 10 years in the German cohort analyzed, corresponds to an average concentration between 2.5 μg/m3 and 15 μg/m3 of total nitrosamines (N-nitrosodimethylamine + N-nitrosomorpholine). This threshold is based on the observation of excess mortality from rare cancers, i.e., cancers of the pharynx and the esophagus observed among 8,933 workers employed between 1950 and 1991.

The measured concentrations of nitrosamines in the warehouse of finished rubber products in the Eastern Townships are in the lower limit of the range of concentrations for which carcinogenic effects were statistically associated with increased cancer in a cohort of workers with an average exposure of about 10 years. Despite this and despite the uncertainties associated with epidemiologic studies published in the literature, the existence of mechanisms of action of carcinogens in human tissue cells similar to those observed in rodents incites caution.

In conclusion, since the career of some workers may extends over a period lasting up to 40 years, it seems reasonable that the average exposure limit to NDMA in ambient air be set at lower than 2.5 μg/m³ in order to protect their health. Thus, we recommend that efforts be made to reduce workers' exposure to daily average concentrations of total nitrosamines below 1 μg/m3 (8 hours/day, 40 hours per week).

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