Elevated mortality from nonalcohol-related chronic liver disease among female rubber workers: Is it associated with exposure to nitrosamines?

Abstract

Background Despite several case reports describing liver toxicity of nitrosamines and the fact that some N‐nitroso compounds are used to induce cirrhosis of the liver in animal models, this association has not been investigated in epidemiological studies. Methods A cohort of 2,875 female rubber workers who were active on January 1, 1976, or hired thereafter, and who had been employed for at least 1 year in one of five plants producing tires or technical rubber goods was followed for mortality from January, 1976, through December, 1991. Work histories were reconstructed using routinely documented “cost center codes” and classified into six work areas. Age and calendar year standardized mortality ratios (SMR) and 95% confidence intervals (95% CI) were calculated and stratified by plant, work area, year of hire, and years of employment in the respective work area. Results The excess mortality from cirrhosis of the liver was most pronounced for nonalcohol‐related cirrhosis of the liver (ICD‐9 571.4–571.9: 10 deaths, SMR 202; 95% CI 97–372). Mortality from alcohol‐related cirrhosis of the liver (ICD‐9 571.0–571.3: 3 deaths, SMR 153; 95% CI 31–446) and from other alcohol‐related diseases (organic psychoses, injury, and poisoning) was not statistically significantly elevated. All 10 cases of nonalcohol‐related cirrhosis had worked in production of technical rubber goods (SMR 279; 95% CI 134–514) and risks increased with earlier years of hire and with longer duration of employment in this work area. Discussion Although our results must be interpreted with caution, they suggest that the observed excess deaths from cirrhosis of the liver are associated with occupational risk factors. In light of additional evidence from case reports and animal data, exposure to nitrosamines may be a plausible risk factor for the observed excess mortality. Am. J. Ind. Med. 35:264–271, 1999. © 1999 Wiley‐Liss, Inc.

A historical cohort mortality study among shipyard workers in Genoa, Italy

“…Occupational exposure to chemicals has been identi®ed as being possibly associated with the occurrence of liver cirrhosis [Dùssing and Skinhùj, 1985]. The California mortality study data set showed the highest mortality rates from liver cirrhosis among construction workers and machinists [Harford and Brooks, 1992] and female rubber workers [Straif et al, 1999]. In addition, with respect to the potential role of viral infections in the etiology of liver cancer and cirrhosis, it is unlikely that the proportion of shipyard workers exposed to viral agents differs from that of the general population.…”

2‐(Allylthio)pyrazine, a Cancer Chemopreventive Agent, Inhibits Liver Fibrosis Induced by Dimethylnitrosamine in Rats: Role of Inhibition of Transforming Growth Factor‐β1 Expression

“…Dimethylnitrosamine is a hepatocarcinogen and hepatotoxicant commonly employed for the induction of experimental liver fibrosis. A recent study revealed that the liver cirrhosis induced by the drug in animal models appeared to parallel with the results of epidemiological studies (Straif et al 1999). Dimethylnitrosamine is toxic to hepatocytes through bioactivation and induces coagulative necrosis in the centrilobular and periportal areas in the liver.…”

“…Epidemiological studies have shown that rubber workers died excessively from liver cirrhosis, which might be associated with the occupational risk factors such as exposure to N-nitroso compounds (Straif et al 1999). Case reports and animal data raised the possibility that exposure to nitrosamines may be a risk factor for incidence of liver cirrhosis and the resultant mortality (Chao et al 1995;Park & Mirer 1996;Straif et al 1999). Nitrosamine, in particular dimethylnitrosamine, is bioactivated by the catalysis of Author for correspondence: Sang Geon Kim, College of Pharmacy, Seoul National University, Sillim-dong, Kwanak-gu, Seoul 151-742, Korea (fax π822 872 1795, e-mail sgk/snu.ac.kr).…”

N ‐nitrosodimethylamine‐Contaminated Valsartan and Risk of Cancer: A Nationwide Study of 1.4 Million Valsartan Users

“… 10 NDMA was also linked to hepatic adverse outcomes in humans after several poisoning incidents 11 , 12 , 13 and was associated with higher excess mortality from nonalcoholic‐related chronic liver disease after occupational exposure. 14 …”