Effects of E-Cigarette Flavoring Chemicals on Human Macrophages and Bronchial Epithelial Cells.

E-cigarettes utilize a wide range of flavoring chemicals with respiratory health effects that are not well understood. In this study, we used pulmonary-associated cell lines to assess the in vitro cytotoxic effects of 30 flavoring chemicals. Human bronchial epithelial cells (BEAS-2B) and both naïve and activated macrophages (THP-1) were treated with 10, 100, and 1000 µM of flavoring chemicals and analyzed for changes in viability, cell membrane damage, reactive oxygen species (ROS) production, and inflammatory cytokine release. Viability was unaffected for all chemicals at the 10 and 100 µM concentrations. At 1000 µM, the greatest reductions in viability were seen with decanal, hexanal, nonanal, cinnamaldehyde, eugenol, vanillin, alpha-pinene, and limonene. High amounts of ROS were elicited by vanillin, ethyl maltol, and the diketones (2,3-pentanedione, 2,3-heptanedione, and 2,3-hexanedione) from both cell lines. Naïve THP-1 cells produced significantly elevated levels of IL-1ß, IL-8, and TNF-α when exposed to ethyl maltol and hexanal. Activated THP-1 cells released increased IL-1ß and TNF-α when exposed to ethyl maltol, but many flavoring chemicals had an apparent suppressive effect on inflammatory cytokines released by activated macrophages, some with varying degrees of accompanying cytotoxicity. The diketones, L-carvone, and linalool suppressed cytokine release in the absence of cytotoxicity. These findings provide insight into lung cell cytotoxicity and inflammatory cytokine release in response to flavorings commonly used in e-cigarettes.

Ethnic differences in diet and associations with clinical markers of prostate disease in New Zealand men.

OBJECTIVE: To examine ethnic differences in diet and dietary associations with clinical markers of prostate disease in New Zealand men. MATERIALS AND METHODS: A total of 1031 males (616 New Zealand European, 230 Maori and 185 Pacific Islands) aged 40-69 years, with no history of prostate cancer, completed a questionnaire covering diet. A serum prostate specific antigen (PSA) blood analysis was also undertaken. Regression models were developed to examine the ethnic-specific levels of selected dietary components, and their relationship with PSA and urinary symptom scores. RESULTS: The results confirmed previously found ethnic differences in the New Zealand diet. Combined tomato intake was positively-correlated with free PSA and % free PSA (p=0.021, r=0.197 and p=0.011, r=0.096 respectively). Beer intake was negatively-correlated with total PSA (p=0.028, r=-0.071) and free PSA (p=0.004, r=-0.094). CONCLUSION: Ethnic differences found in the consumption of foods (associated with prostate cancer) highlight the possible importance of dietary interactions for ethnic prostate cancer risk. Associations between specific foods and PSA warrant further investigation.

Demographic and clinical factors as determinants of serum levels of prostate specific antigen and its derivatives.

BACKGROUND: To characterise the association between demographic and clinical factors and levels of total prostate specific antigen (tPSA) and its molecular derivatives complexed PSA (cPSA), free PSA (fPSA) and the ratio of free to total PSA (%fPSA)] in New Zealand Maori, Pacific Islanders and Europeans, in order to determine whether reported ethnic differences in PSA can be explained by lifestyle and social factors. MATERIALS AND METHODS: Demographic and clinical factors were examined in relation to tPSA, fPSA and cPSA levels, in 1405 Maori, Pacific Island and New Zealand European men with no clinical evidence of prostate cancer, in the Wellington region of New Zealand. Any associations between levels of PSA and PSA derivatives and body mass index, smoking status, family cancer history, non-steroidal anti-inflammatory/vitamin supplement usage, number of sexual partners, age at first intercourse, previous vasectomy, marital/partnership status, educational level and socioeconomic status were investigated by backwards stepwise regression analysis, correcting for age, ethnicity and urinary symptoms. RESULTS: Not being married/partnered was associated with increased tPSA, fPSA and cPSA. tPSA and cPSA decreased with regular non-steroidal anti-inflammatory use. cPSA was decreased in subjects with a first degree relative with any form of cancer. tPSA and fPSA were decreased if the body mass index was > 34. fPSA and %fPSA were decreased in current and former smokers. CONCLUSION: Demographic and clinical factors appear to have a significant effect on levels of PSA and its various derivatives and may account for previously observed ethnic differences. It is important that these associations are taken into account when comparing individual PSA results with standard reference ranges.

Assessment of ethnic variation in serum levels of total, complexed and free prostate specific antigen. Comparison of Maori, Pacific Island and New Zealand European populations.

AIMS: To determine whether age-adjusted levels of serum total (tPSA) and complexed (cPSA) prostate specific antigen and the ratio of free to tPSA (%fPSA) differ by ethnic group independent of symptomatic disease. METHODS: The serum levels of tPSA, cPSA, and %fPSA in relation to age, ethnicity and obstructive urinary symptoms were examined in 1405 Maori, Pacific Island and New Zealand European men in the Wellington region of New Zealand, and indicative reference range estimates produced. Participants were non-randomly selected from two study populations. RESULTS: tPSA and cPSA increased with age while %fPSA decreased with age in all ethnic groups. Maori showed higher tPSA values in the 60-69 age group than other ethnic groups. cPSA increased more rapidly with age in Maori than in New Zealand Europeans or Pacific Islanders. %fPSA differed according to age across all three ethnic groups. The median and 5th percentile Pacific Island %fPSA values were higher in comparison to the %fPSA reference ranges of all other ethnic groups and were also higher than those reported in other studies. Once adjusted for urinary symptom score, only %fPSA in Pacific Island subjects remained significantly higher than that in New Zealand Europeans (P<0.001). CONCLUSIONS: Our study indicates that %fPSA differs by ethnicity independent of symptomatic prostate disease.

Consideration of rat chronic progressive nephropathy in regulatory evaluations for carcinogenicity.

Chronic progressive nephropathy (CPN) is a spontaneous renal disease of rats which can be a serious confounder in toxicology studies. It is a progressive disease with known physiological factors that modify disease progression, such as high dietary protein. The weight of evidence supports an absence of a renal counterpart in humans. There is extensive evidence that advanced CPN, particularly end-stage kidney, is a risk factor for development of a background incidence of atypical tubule hyperplasia and renal tubule tumors (RTT). The likely cause underlying this association with tubule neoplasia is the long-term increased tubule cell proliferation that occurs throughout CPN progression. As a variety of chemicals are able to exacerbate CPN, there is a potential for those exacerbating the severity up to and including end-stage kidney to cause a marginal increase in RTT and their precursor lesions. Extensive statistical analysis of National Toxicology Program studies shows a strong correlation between high-grade CPN, especially end-stage CPN, and renal tumor development. CPN as a mode of action (MOA) for rat RTT has received attention from regulatory authorities only recently. In the absence of toxic effects elsewhere, this does not constitute a carcinogenic effect of the chemical but can be addressed through a proposed MOA approach for regulatory purposes to reach a decision that RTT, developing as a result of CPN exacerbation in rats, have no relevance for human risk assessment. Guidelines are proposed for evaluation of exacerbation of CPN and RTT as a valid MOA for a given chemical.

Development of acute inhalation reference exposure levels (RELs) to protect the public from predictable excursions of airborne toxicants.

Uniform guidelines have been developed for the derivation of 1-h acute inhalation reference exposure levels (RELs) applicable to the general public exposed routinely to hazardous substances released into the environment. Existing acute exposure guidance values developed by other organizations have been examined, and strengths and weaknesses in these existing guidelines have been identified. The results of that examination have led to the development of a reproducible and resource-intensive methodology to calculate acute inhalation RELs for 41 prioritized chemicals. Approaches to estimating levels protective against mild and severe acute effects are discussed in this report. The default methodology is the no-observed-adverse-effect level (NOAEL)/uncertainty factor (UF) approach using mainly reports in the peer-reviewed toxicological and medical literature. For two well-studied chemicals, ammonia and formaldehyde, the data allowed a benchmark dose (or concentration) methodology, as a departure from the default options, to be used. However, better human dose-response data from, for example, improved workplace monitoring correlated with symptoms, and more extensive epidemiological studies are needed before the departure from default approaches can be expanded to more substances.