Biomarkers Of Toxicant Exposure Research Articles

Changes in Biomarkers of Exposure on Switching From a Conventional Cigarette to Tobacco Heating Products: A Randomized, Controlled Study in Healthy Japanese Subjects.

BackgroundSmoking is a leading cause of numerous human disorders including pulmonary disease, cardiovascular disease, and cancer. Disease development is primarily caused by exposure to cigarette smoke constituents, many of which are known toxicants. Switching smokers to modified risk tobacco products (MRTPs) has been suggested as a potential means to reduce the risks of tobacco use, by reducing such exposure.MethodsThis randomized, controlled study investigated whether biomarkers of toxicant exposure (BoE) were reduced when smokers switched from smoking combustible cigarettes to using a novel (glo™/THP1.0) or in-market comparator (iQOS/THS) tobacco heating product (THP). One hundred eighty Japanese smokers smoked combustible cigarettes during a 2-day baseline period, followed by randomization to either continue smoking cigarettes, switch to using mentholated or non-mentholated variants of glo™, switch to using a non-mentholated variant of iQOS, or quit nicotine and tobacco product use completely for 5 days. Baseline and post-randomization 24-h urine samples were collected for BoE analysis. Carbon monoxide was measured daily in exhaled breath (eCO).ResultsOn day 5 after switching, urinary BoE (excluding for nicotine) and eCO levels were significantly (p < .05) reduced by medians between 20.9% and 92.1% compared with baseline in all groups either using glo™ or iQOS or quitting tobacco use. Between-group comparisons revealed that the reductions in the glo™ groups were similar (p > .05) to quitting in many cases.Conclusionsglo™ or iQOS use for 5 days reduced exposure to smoke toxicants in a manner comparable to quitting tobacco use. THPs are reduced exposure tobacco products with the potential to be MRTPs.ImplicationsThis clinical study demonstrates that when smokers switched from smoking combustible cigarettes to using tobacco heating products their exposure to smoke toxicants was significantly decreased. In many cases, this was to the same extent as that seen when they quit smoking completely. This may indicate that these products have the potential to be reduced exposure and/or reduced risk tobacco products when used by smokers whose cigarette consumption is displaced completely.Clinical Trial RegistrationsISRCTN14301360 and UMIN000024988.

Hexavalent chromium reduces larval growth and alters gene expression in mummichog (Fundulus heteroclitus)

Hexavalent chromium [Cr(VI)] is a common bioavailable metal ion that causes oxidative stress, DNA adducts, and perturbs gene expression. Changes in gene expression are useful biomarkers of toxicant exposure that provide information about an organism's health, adaptability, and toxicant-specific effects. Therefore, we developed a cDNA array for the estuarine sentinel species mummichog (Fundulus heteroclitus). Mummichog larvae were exposed to concentrations ranging from 0 to 24 mg/L (462 microM) of Cr(VI) for 30 d, and growth was measured to determine the no-observable-effect concentration (1.5 mg/L) and the lowest-observable-effect concentration (3 mg/L). Body burdens from Cr(VI)-exposed fish showed a dose-dependent increase and were inversely correlated to body weight. Mummichog larvae exposed to Cr(VI) differentially expressed 16 genes in a dose-dependent manner, including GLUT-2, L-FABP, ATPase synthase 8, type II keratin, TBT-binding protein, and complement component C3-2. Many of these genes are involved in energy metabolism or growth, which is consistent with the reduced growth observed. In subsequent experiments, adults were exposed to Cr(VI) for 7 d at 0, 1.5, or 3 mg/L, because adult mummichog are used in monitoring Superfund sites. Hexavalent chromium altered the expression of 10 genes in adult liver, including HGFA, H-FABP, and complement component C3-2. Many of these genes also are involved in energy metabolism. The mummichog arrays provide a potential mechanism for the effects of Cr(VI) on growth. We anticipate using these arrays and the data they provide to monitor effects at polluted sites, to assess the bioavailability of chromium at these sites, and to investigate the efficacy of remediation in chromium-polluted estuaries.

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Background An essential component of evaluating potential modified risk tobacco products is to determine how consumers use the product and resulting effects on biomarkers of toxicant exposure. Study design Cigarette smokers (n=391) recruited in Minnesota and Oregon were randomised to either snus or 4 mg nicotine gum for 12 weeks. Participants were instructed to completely switch from cigarettes to these products. Urine samples were collected to analyse for carcinogenic tobacco-specific nitrosamine metabolites (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and N′-nitrosonornicotine and their glucuronides) and nicotine metabolites (total cotinine and nicotine equivalents) levels. Results Of the 391 participants randomised, 52.9% were male, the mean±SD age was 43.9±12.5 years, baseline number of cigarettes/day was 18.0±6.5 and Fagerstrom Test for Nicotine Dependence score was 5.1±2.0. The mean±SD number of snus pouches used/week at week 6 prior to tapering was 39.1±24.0 and nicotine gum pieces used was 37.6±26.3. Dual use of cigarettes and these products were observed in 52.9% and 58.2% of those assigned to snus and nicotine gum, respectively, at week 12. The end of treatment biochemically verified (carbon monoxide, CO Conclusions Snus performed similarly to nicotine gum in cigarette smokers who were interested in completely switching to these products, but was associated with less satisfaction and greater toxicant exposure than nicotine gum. Trial registration number NCT: 00710034.

Biomarkers of reproductive toxicity

A biomarker can be broadly defined as any biological index capable of being measured, which is associated with or indicative of a defined biological endpoint such as a developmental or disease stage. Identification and verification of anatomical, endocrine, cellular and molecular biomarkers is crucial for successful clinical diagnosis and treatment of toxicity and disease, as well as basic toxicological, epidemiological and other research. Various biomarkers of reproductive development and health have been identified, including those associated with pubertal development, adult reproductive health and pregnancy outcome. Herein we discuss those in situ biomarkers which have been more closely associated with toxicant action on the reproductive system. Biomarkers of toxicant exposure and susceptibility are addressed, but the majority of the review focuses on those biomarkers which may prove useful for determining current pathophysiological status or predicting future adverse outcomes. In males these are primarily associated with altered spermatogenesis and sperm parameters, and in females with altered endocrine function. We conclude that although few robust in situ biomarkers are currently available which are specific for toxicant exposure, susceptibility or effect in reproductive systems, there is expectation that post-genomic technologies offer a new paradigm for identifying and verifying such biomarkers as may exist.

Lymphocyte proliferation assays as potential biomarkers for toxicant exposures

Recently there has been interest in developing assays that can be used as indicators (biomarkers) of exposure to toxic agents. We have been exploring the potential utility of three lymphocyte proliferation assays [the responses of B lymphocytes to the mitogen lipopolysaccharide (LPS), the responses of T lymphocytes to the mitogen concanavalin A (ConA), and the responses of T lymphocytes to antigenic stimuli in a mixed lymphocyte culture (MLC) assay] as biomarkers of toxicant exposure. Studies were initiated to assess the applicability and specificity of these assays and to investigate the mechanisms by which toxicants alter lymphocyte proliferation. All studies were performed using cells isolated from Fischer 344 rats. To assess applicability, mitogen assays were performed using in vitro exposures to eight different toxicants: hydroquinone, benzoquinone, Aroclor 1254, styrene oxide, and the salts of mercury, cadmium, chromate, and nickel. In vitro concentrations spanned five orders of magnitude (100 to 0.01 mg/l). At the lowest concentration tested, all eight compounds induced changes in at least one mitogen assay, indicating that these assays may be applicable to a wide range of toxicants. Variations of the ConA and MLC assays were used to test for specificity. In both assays, splenocytes taken from rats exposed in vivo to either chromate or to cadmium responded differently when the cells were cocultured with exogenously added chromate or cadmium ions, indicating that it may be possible to detect exposure to a specific toxicant by performing modified lymphocyte proliferation assays. In the mechanistic studies, splenocytes from cadmium and chromate-treated rats altered the ConA-induced proliferation of cocultured syngeneic cells. In addition, the antigenicity of splenocytes isolated from cadmium-treated rats was enhanced when these cells were used as stimulators for allogeneic splenocytes. The results of these studies indicate that lymphocyte proliferation assays may be useful for detecting exposure to a wide range of toxicants and that variations of these assays may be useful for implementing immunologically based tests for detecting exposures to specific chemicals.