A review of the control of carcinogenic exposures using the TLV approach presents a prospect of limited effectiveness. With asbestos, as with any carcinogen, no threshold is known below which no health effect may be manifest. At best, we have only limited dose-response information at levels much above those of practical concern. In the case of asbestos, current exposures can only be described crudely at any level of exposure, and health effects are only known for past high, but ill-defined, exposures. Limited information exists on the effects of synergistic interactions with other materials. The current U.S. TLV, based on data concerned with occurrence of asbestosis, has not been evaluated with regard to possible effectiveness in the prevention of asbestos cancer. Yet cancer is the heart of the asbestos-hazard problem. Finally, enforcement of the existing TLV, especially for asbestos has been limited, frequently absent, and often ineffective. Workers are exposed in many situations to levels much above the current standard. As discouraging as this picture may seem, a TLV can be useful for stimulating the development and application of engineering-control procedures. The application of these procedures, however, must be specified and mandated in future standards to lower worker exposures to the minimum commensurate with existing technology. As technology is developed that makes lower exposure levels possible in a large part of the industry, TLVs should be reduced to take advantage of that technology.
The impact of tobacco use and coffee and tea intake on the risk of colorectal cancer is unclear. Previous research has suggested that coffee may be protective against these cancers, and investigation regarding tea or cigarette smoking has yielded inconsistent results. To clarify these issues, we evaluated coffee and tea intake and tobacco smoking as risk factors for cancer of the colon and rectum in a population-based case-control study from Stockholm, Sweden. Cases were ascertained from the regional cancer registry, and controls identified through population registers. Subjects completed a questionnaire requesting information regarding foods and beverages consumed, exercise, tobacco use, and personal characteristics. Logistic regression modelling was used to compute odds ratios. A total of 352 cases of colon cancer, 217 cases of rectal cancer, and 512 controls took part. High coffee intake was negatively associated with the risk of colon cancer: the odds ratio for those drinking 6 or more cups per day was 0.55 (95% confidence interval, 0.31-0.96) compared to those drinking one or fewer. There was no association with rectal cancer. For tea, the associations were the opposite: there was no association with colon cancer risk, but the odds ratio for rectal cancer was 0.56 (95% confidence interval, 0.34-0.90) for those drinking 2 or more cups per day compared with those drinking none. Smokers of 11 or more cigarettes per day had a 20 to 30% reduction in the risk of colon and rectal cancer, but these findings were consistent with chance. There was no association of long-term cigarette smoking with risk.
To study the combined effect of smoking and human papillomavirus (HPV) type 16 infection in high-grade cervical intraepithelial neoplasia, we analyzed data from a Norwegian population-based case-control study including 90 patients and 216 controls, 20-44 years of age. We assessed HPV-16 status both by polymerase chain reaction detecting virus DNA and by enzyme-linked immunosorbent assay detecting antibodies against virus capsid. Smoking was associated with cervical intraepithelial neoplasia grade II-III in HPV-16-positive individuals. Using the jointly unexposed (HPV-16 DNA-negative never-smokers) as the reference group, we determined the risk of cervical intraepithelial neoplasia grade II-III in HPV-16 DNA-positive never-smokers and HPV-16 DNA-positive ever-smokers (odds ratio = 15.7; 95% confidence limits = 3.2, 76.5, and odds ratio = 65.9; 95% confidence limits = 22.3, 194.3, respectively). The estimated proportion of cases among HPV-16-positive smokers that is attributable to the interaction between the two causes is 74%, based on HPV-16 DNA positivity.
CYP2C9 enzymes are important in the metabolism of procarcinogenic chemicals such as polycyclic aromatic hydrocarbons (PAHs) found in tobacco smoke. Two functional variants in the CYP2C9 gene (CYP2C9*2 and CYP2C9*3) are known to be associated with decreased enzyme activity towards tolbutamide and warfarin, while this has not been investigated for PAHs. We hypothesised that these two variants in the CYP2C9 gene influence risk of tobacco-related cancer.
In a prospective study of the general population (n=10 392) with 60 years of follow-up, the Copenhagen City Heart Study, we associated two variants of CYP2C9 (CYP2C9*2 and CYP2C9*3) with risk of tobacco-related cancer and all cancer. All results were re-tested in a cross-sectional study of the general population (n=36 856), the Copenhagen General Population Study.
We found no association between any of the CYP2C9 genotypes and risk of tobacco-related cancer, individual tobacco-related cancers, or all cancer. For the combined carriers (any CYP2C9*2 or CYP2C9*3 heterozygotes or homozygotes) vs. non-carriers we had 90% statistical power to exclude measures of relative risks below/above 0.8/1.2 and 0.9/1.1 in the Copenhagen City Heart Study and below/above 0.8/1.3 and 0.9/1.1 in the Copenhagen General Population Study for tobacco-related cancer and all cancer, respectively.
Genetic variations in CYP2C9 do not affect risk of tobacco-related cancers.
To estimate the exposure-response function associating polycyclic aromatic hydrocarbon (PAH) exposure and lung cancer, with consideration of smoking.
Mortality, occupational exposure and smoking histories were ascertained for a cohort of 16,431 persons (15,703 men and 728 women) who had worked in one of four aluminium smelters in Quebec from 1950 to 1999. A variety of exposure-response functions were fitted to the cohort data using generalised relative risk models.
In 677 lung cancer cases there was a clear trend of increasing risk with increasing cumulative exposure to PAH measured as benzo(a)pyrene (BaP). A linear model predicted a relative risk of 1.35 (95% CI 1.22 to 1.51) at 100 microg/m(-3) BaP years, but there was a significant departure from linearity in the direction of decreasing slope with increasing exposures. Among the models tried, the best fitting were a two-knot cubic spline and a power curve (RR = (1+bx)(p)), the latter predicting a relative risk of 2.68 at 100 microg/m(-3) BaP years. Additive models and multiplicative models for combining risks from occupational PAH and smoking fitted almost equally well, with a slight advantage to the additive.
Despite the large cohort with long follow-up, the shape of the exposure-response function and the mode of combination of risks due to occupational PAH and smoking remains uncertain. If a linear exposure-response function is assumed, the estimated slope is broadly in line with the estimate from a previous follow-up of the same cohort, and somewhat higher than the average found in a recent meta-analysis of lung cancer studies.
Comment In: Occup Environ Med. 2009 Nov;66(11):716-719837902
Two functional polymorphisms of the microsomal epoxide hydrolase (mEH) gene (EPHX1), Tyr113His (rs1051740) and His139Arg (rs2234922), have variably been found to influence susceptibility to various cancer forms. We tested whether genetically lowered mEH activity affects risk of developing cancer in the general population.
We genotyped 47,089 individuals from the Danish general population for the Tyr113His and His139Arg polymorphisms in the EPHX1 gene and divided them into groups with predicted fast, intermediate, and slow mEH activity. Using Cox proportional hazards models, we calculated HRs for 26 individual cancer diagnoses and for groups of any cancer, tobacco-related cancers, estrogen-related female cancers, and other cancers.
Of the 47,089 individuals, 7,590 experienced a cancer event, and of these, 1,466 were tobacco-related. After multifactorial adjustment, the HRs (95% CI) for tobacco-related cancer were 1.1 (0.8-1.5) and 1.5 (1.1-2.0) in individuals with intermediate and slow mEH activity versus individuals with the fast phenotype (P(trend) = 0.003). The corresponding HRs among ever-smokers were 1.1 (0.8-1.5) and 1.5 (1.1-2.0; P(trend) = 0.003), whereas HRs among never-smokers did not differ from 1.0.
Our results indicate that genetically lowered mEH activity is associated with increased risk of developing tobacco-related cancer among smokers in the general population; however, additional studies are needed to confirm our findings.
To our knowledge, this is the largest study to investigate the association of mEH phenotype and genotype with tobacco-related cancers combined in the general population.
Exposure to estrogens is associated with an increased risk of breast cancer. Our laboratory has shown that the ACI rat is uniquely susceptible to 17beta-estradiol (E2)-induced mammary cancer. We previously mapped two loci, Emca1 and Emca2 (estrogen-induced mammary cancer), that act independently to determine susceptibility to E2-induced mammary cancer in crosses between the susceptible ACI rat strain and the genetically related, but resistant, Copenhagen (COP) rat strain. In this study, we evaluate susceptibility to E2-induced mammary cancer in a cross between the ACI strain and the unrelated Brown Norway (BN) rat strain. Whereas nearly 100% of the ACI rats developed mammary cancer when treated continuously with E2, BN rats did not develop palpable mammary cancer during the 196-day course of E2 treatment. Susceptibility to E2-induced mammary cancer segregated as a dominant or incompletely dominant trait in a cross between BN females and ACI males. In a population of 251 female (BN x ACI)F(2) rats, we observed evidence for a total of five genetic determinants of susceptibility. Two loci, Emca4 and Emca5, were identified when mammary cancer status at sacrifice was evaluated as the phenotype, and three additional loci, Emca6, Emca7, and Emca8, were identified when mammary cancer number was evaluated as the phenotype. A total of three genetic interactions were identified. These data indicate that susceptibility to E2-induced mammary cancer in the BN x ACI cross behaves as a complex trait controlled by at least five loci and multiple gene-gene interactions.