Carcinogenic Endpoints Research Articles

The Known and Unknown: Investigating the Carcinogenic Potential of Plastic Additives.

Microplastics are routinely ingested and inhaled by humans and other organisms. Despite the frequency of plastic exposure, little is known about its health consequences. Of particular concern are plastic additives─chemical compounds that are intentionally or unintentionally added to plastics to improve functionality or as residual components of plastic production. Additives are often loosely bound to the plastic polymer and may be released during plastic exposures. To better understand the health effects of plastic additives, we performed a comprehensive literature search to compile a list of 2,712 known plastic additives. Then, we performed an integrated toxicogenomic analysis of these additives, utilizing cancer classifications and carcinogenic expression pathways as a primary focus. Screening these substances across two chemical databases revealed two key observations: (1) over 150 plastic additives have known carcinogenicity and (2) the majority (∼90%) of plastic additives lack data on carcinogenic end points. Analyses of additive usage patterns pinpointed specific polymers, functions, and products in which carcinogenic additives reside. Based on published chemical-gene interactions, both carcinogenic additives and additives with unknown carcinogenicity impacted similar biological pathways. The predominant pathways involved DNA damage, apoptosis, the immune response, viral diseases, and cancer. This study underscores the urgent need for a systematic and comprehensive carcinogenicity assessment of plastic additives and regulatory responses to mitigate the potential health risks of plastic exposure.

Arsenic and cancer: Evidence and mechanisms.

Arsenic is a potent carcinogen and poses a significant health concern worldwide. Exposure occurs through ingestion of drinking water and contaminated foods and through inhalation due to pollution. Epidemiological evidence shows arsenic induces cancers of the skin, lung, liver, and bladder among other tissues. While studies in animal and cell culture models support arsenic as a carcinogen, the mechanisms of arsenic carcinogenesis are not fully understood. Arsenic carcinogenesis is a complex process due its ability to be metabolized and because of the many cellular pathways it targets in the cell. Arsenic metabolism and the multiple forms of arsenic play distinct roles in its toxicity and contribute differently to carcinogenic endpoints, and thus must be considered. Arsenic generates reactive oxygen species increasing oxidative stress and damaging DNA and other macromolecules. Concurrently, arsenic inhibits DNA repair, modifies epigenetic regulation of gene expression, and targets protein function due its ability to replace zinc in select proteins. While these mechanisms contribute to arsenic carcinogenesis, there remain significant gaps in understanding the complex nature of arsenic cancers. In the future improving models available for arsenic cancer research and the use of arsenic induced human tumors will bridge some of these gaps in understanding arsenic driven cancers.

Modeling Radiation-Induced Neoplastic Cell Transformation In Vitro and Tumor Induction In Vivo with the Local Effect Model.

Ionizing radiation induces DNA damage to cycling cells which, if left unrepaired or misrepaired, can cause cell inactivation or heritable, viable mutations. The latter can lead to cell transformation, which is thought to be an initial step of cancer formation. Consequently, the study of radiation-induced cell transformation promises to offer insights into the general properties of radiation carcinogenesis. As for other end points, the effectiveness in inducing cell transformation is elevated for radiation qualities with high linear energy transfer (LET), and the same is true for cancer induction. In considering DNA damage as a common cause of both cell death and transformations, a worthwhile approach is to apply mathematical models for the relative biological effectiveness (RBE) of cell killing to also assess the carcinogenic potential of high-LET radiation. In this work we used an established RBE model for cell survival and clinical end points, the local effect model (LEM), to estimate the transformation probability and the carcinogenic potential of ion radiation. The provided method consists of accounting for the competing processes of cell inactivation and induction of transformations or carcinogenic events after radiation exposure by a dual use of the LEM. Correlations between both processes inferred by the number of particle impacts to individual cells were considered by summing over the distribution of hits that individual cells receive. RBE values for cell transformation in vitro were simulated for three independent data sets, which were also used to gauge the approach. The simulations reflect the general RBE systematics both in magnitude and in energy and LET dependence. To challenge the developed method, in vivo carcinogenesis was investigated using the same concepts, where the probability for cancer induction within an irradiated organ was derived from the probability of finding carcinogenic events in individual cells. The predictions were compared with experimental data of carcinogenesis in Harderian glands of mice. Again, the developed method shows the same characteristics as the experimental data. We conclude that the presented method is helpful to predictively assess RBE for both neoplastic cell transformation and tumor induction after ion exposure within a wide range of LET values. The theoretical concept requires a non-linear component in the photon dose response for carcinogenic end points as a precondition for the observed enhanced effects after ion exposure, thus contributing to a long debate in epidemiology. Future work will use the method for assessing cancer induction in radiation therapy and exposure scenarios frequently discussed in radiation protection.

Discriminating Spontaneous From Cigarette Smoke and THS 2.2 Aerosol Exposure-Related Proliferative Lung Lesions in A/J Mice by Using Gene Expression and Mutation Spectrum Data.

Mice, especially A/J mice, have been widely employed to elucidate the underlying mechanisms of lung tumor formation and progression and to derive human-relevant modes of action. Cigarette smoke (CS) exposure induces tumors in the lungs; but, non-exposed A/J mice will also develop lung tumors spontaneously with age, which raises the question of discriminating CS-related lung tumors from spontaneous ones. However, the challenge is that spontaneous tumors are histologically indistinguishable from the tumors occurring in CS-exposed mice. We conducted an 18-month inhalation study in A/J mice to assess the impact of lifetime exposure to Tobacco Heating System (THS) 2.2 aerosol relative to exposure to 3R4F cigarette smoke (CS) on toxicity and carcinogenicity endpoints. To tackle the above challenge, a 13-gene gene signature was developed based on an independent A/J mouse CS exposure study, following by a one-class classifier development based on the current study. Identifying gene signature in one data set and building classifier in another data set addresses the feature/gene selection bias which is a well-known problem in literature. Applied to data from this study, this gene signature classifier distinguished tumors in CS-exposed animals from spontaneous tumors. Lung tumors from THS 2.2 aerosol-exposed mice were significantly different from those of CS-exposed mice but not from spontaneous tumors. The signature was also applied to human lung adenocarcinoma gene expression data (from The Cancer Genome Atlas) and discriminated cancers in never-smokers from those in ever-smokers, suggesting translatability of our signature genes from mice to humans. A possible application of this gene signature is to discriminate lung cancer patients who may benefit from specific treatments (i.e., EGFR tyrosine kinase inhibitors). Mutational spectra from a subset of samples were also utilized for tumor classification, yielding similar results. “Landscaping” the molecular features of A/J mouse lung tumors highlighted, for the first time, a number of events that are also known to play a role in human lung tumorigenesis, such as Lrp1b mutation and Ros1 overexpression. This study shows that omics and computational tools provide useful means of tumor classification where histopathological evaluation alone may be unsatisfactory to distinguish between age- and exposure-related lung tumors.

A look beyond the priority: A systematic review of the genotoxic, mutagenic, and carcinogenic endpoints of non-priority PAHs.

Knowledge of the toxic potential of polycyclic aromatic hydrocarbons (PAHs) has increased over time. Much of this knowledge is about the 16 United States - Environmental Protection Agency (US - EPA) priority PAHs; however, there are other US - EPA non-priority PAHs in the environment, whose toxic potential is underestimated. We conducted a systematic review of invitro, invivo, and in silico studies to assess the genotoxicity, mutagenicity, and carcinogenicity of 13 US - EPA non-priority parental PAHs present in the environment. Electronic databases, such as Science Direct, PubMed, Scopus, Google Scholar, and Web of Science, were used to search for research with selected terms without time restrictions. After analysis, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol, 249 articles, published between 1946 and 2020, were selected and the quality assessment of these studies was performed. The results showed that 5-methylchrysene (5-MC), 7,12-dimethylbenz[a]anthracene (7,12-DMBA), cyclopenta[cd]pyrene (CPP), and dibenzo[al]pyrene (Db[al]P) were the most studied PAHs. Moreover, 5-MC, 7,12-DMBA, benz[j]aceanthrylene (B[j]A), CPP, anthanthrene (ANT), dibenzo[ae]pyrene (Db[ae]P), and Db[al]P have been reported to cause mutagenic effects and have been being associated with a risk of carcinogenicity. Retene (RET) and benzo[c]fluorene (B[c]F), the least studied compounds, showed evidence of a strong influence on the mutagenicity and carcinogenicity endpoints. Overall, this systematic review provided evidence of the genotoxic, mutagenic, and carcinogenic endpoints of US - EPA non-priority PAHs. However, further studies are needed to improve the future protocols of environmental analysis and risk assessment in severely exposed populations.

Solar photo-Fenton treatment of the anti-cancer drug anastrozole in different aqueous matrices at near-neutral pH: Transformation products identification, pathways proposal, and in silico (Q)SAR risk assessment

Anastrozole (ANZ) is a breast cancer drug that was introduced onto the pharmaceutical market in the 1990s and is still one of the most widely consumed cytotoxic compounds. Due to the persistence of the drug, its continued presence after passing through wastewater treatment plants can lead to harm to aquatic environments. The present study investigates use of the solar photo-Fenton (SPF) process applied for ANZ degradation, considering the fate of ANZ and its transformation products (TPs). The SPF process was performed using different concentrations of ferrous iron (Fe2+) and H2O2 in solutions produced with deionized water (DW) and hospital wastewater (HWW), at pH close to neutrality. When solar irradiation in the SPF process was carried out the best ANZ removal rates were found under the following conditions: (i) for the DW matrix, [ANZ]0 = 50 μg L−1, [Fe2+] = 5 mg L−1, and [H2O2]0 = 25 mg L−1, achieving 95% primary ANZ elimination; (ii) for the HWW matrix, [ANZ]0 = 50 μg L−1, [Fe2+] = 10 mg L−1(multiple additions), and [H2O2]0 = 25 mg L−1, achieving 51% primary ANZ elimination. LC-QTOF MS analysis allowed to identify tentatively five transformation products (TPs) formed during the ANZ degradation process in DW, and two TPs when HWW was used. The main proposed degradation pathways were demethylation and hydroxylation. Different in silico models free available (quantitative) structure-activity relationship ((Q)SAR) software were used to predict the ecotoxicities and environmental fates of ANZ and the TPs. The in silico (Q)SAR predictions indicated that ANZ and the TPs were non-biodegradable compounds. In silico (Q)SAR predictions for mutagenicity and carcinogenicity end-points identified some TPs that require further study. Attention is drawn to the formation of several TPs for which statistical and rule-based positive alerts for mutagenic activities were found, requiring further confirmatory in vitro validation tests.

Occurrence of Acrylamide in Italian Baked Products and Dietary Exposure Assessment.

Acrylamide (AA) is a neo-formed toxic compound that develops in foods during cooking at temperatures above 120 °C. AA shows in vivo neurotoxic and carcinogenic effects, and it is potentially carcinogenic for humans. Its occurrence is common in baked food, such as bread and similar products. This study set out to analyze bread and sweets from the Italian market to evaluate the effects of the benchmark thresholds set by EU Regulation 2017/2158 and to ascertain the exposure of the Italian population to AA, across three age groups, through the consumption of baked products, according to the margin of exposure (MOE) approach. Two hundred samples were tested, and the content of AA ranged from 31 to 454 µg/kg for bread and products thereof and from 204 to 400 µg/kg for the sweets category. The exposure data did not show any neurotoxic health concern, whereas the MOE related to the carcinogenic endpoint is well below the minimum safety value of 10,000.

Degradation of the anticancer drug flutamide by solar photo-Fenton treatment at near-neutral pH: Identification of transformation products and in silico (Q)SAR risk assessment

Flutamide (FLUT) is a non-steroidal drug mainly used in the treatment of prostate cancer and has been detected in the aquatic environment at ng L−1 levels. The environmental fate and effects of FLUT have not yet been studied. Conventional treatment technologies fail to completely remove pharmaceuticals, so the solar photo-Fenton process (SPF) has been proposed as an alternative. In this study, the degradation of FLUT, at two different initial concentrations in ultra-pure water, was carried out by SPF. The initial SPF conditions were pH0 5, [Fe2+]0 = 5 mg L−1, and [H2O2]0 = 50 mg L−1. Preliminary elimination rates of 53.4% and 73.4%. The kinetics of FLUT degradation could be fitted by a pseudo-first order model and the kobs were 6.57 × 10−3 and 9.13 × 10−3 min−1 t30W and the half-life times were 95.62 and 73.10 min t30W were achieved for [FLUT]0 of 5 mg L−1 and 500 μg L−1, respectively. Analysis using LC-QTOF MS identified thirteen transformation products (TPs) during the FLUT degradation process. The main degradation pathways proposed were hydroxylation, hydrogen abstraction, demethylation, NO2 elimination, cleavage, and aromatic ring opening. Different in silico (quantitative) structure-activity relationship ((Q)SAR) freeware models were used to predict the toxicities and environmental fates of FLUT and the TPs. The in silico predictions indicated that these substances were not biodegradable, while some TPs were classified near the threshold point to be considered as PBT compounds. The in silico (Q)SAR predictions gave positive alerts concerning the mutagenicity and carcinogenicity endpoints. Additionally, the (Q)SAR toolbox software provided structural alerts corresponding to the positive alerts obtained with the different mutagenicity and carcinogenicity models, supporting the positive alerts with more proactive information.

Development of an inhalation unit risk factor for ethylene dibromide

The Texas Commission on Environmental Quality (TCEQ) follows standard scientific methods to develop up-to-date toxicity factors for chemicals emitted in the state of Texas. An inhalation unit risk factor (URF) was developed for ethylene dibromide (EDB, CAS 106-93-4) based on an increased incidence of nasal cavity adenocarcinomas observed in female rats in a 2-year inhalation cancer bioassay conducted by the National Toxicology Program (NTP). The NTP study provided evidence of several EDB-induced tumors in male and female rats and in female mice. Tumor incidences that were statistically increased at the low dose and that showed a statistically significant increasing trend were considered in identifying the critical effect. Following benchmark concentration (BMC) modeling and animal-to-human dosimetric adjustments, the increased incidence of nasal cavity adenocarcinomas observed in female rats was determined to be the most sensitive tumorigenic effect in the most sensitive species and sex and was utilized as the carcinogenic endpoint for the development of the URF. The 95% lower confidence limit of the BMC at the 10% excess risk level (BMCL10 of 292.8 ppb) was determined for calculation of the URF. The resulting URF based on increased nasal cavity adenocarcinomas observed in female rats is 3.4E-04 per ppb (4.4E-05 per µg/m3). The lifetime air concentration corresponding to a no significant excess risk level of one in 100,000 is 0.029 ppb (0.22 µg/m3), which is considered sufficiently health-protective for use in protecting the general public against the potential carcinogenic effects of chronic exposure to EDB in ambient air.

Chemical and in vitro biological information to predict mouse liver toxicity using recursive random forests

In this study, recursive random forests were used to build classification models for mouse liver toxicity. The mouse liver toxicity endpoint (67 toxic and 166 non-toxic) was a composition of four in vivo chronic systemic and carcinogenic toxicity endpoints (non-proliferative, neoplastic, proliferative and gross pathology). A multiple under-sampling approach and a shifted classification threshold of 0.288 (non-toxic < 0.288 and toxic ≥ 0.288) were used to cope with the unbalanced data. Our study showed that recursive random forests are very efficient in variable selection and for the development of predictive in silico models. Generally, over 95% redundant descriptors could be reduced from modelling for all the chemical, biological and hybrid models in this study. The predictive performance of chemical models (CCR of 0.73) is comparable with hybrid model performance (CCR of 0.74). Descriptors related to the octanol–water partition coefficient are vital for model performance. The in vitro endpoint of CYP2A2 played a key role in the development and interpretation of hybrid models. Identifying high-throughput screening assays relevant to liver toxicity would be key for improving in silico models of liver toxicity.

Development of an inhalation unit risk factor for ethylene dichloride

The Texas Commission on Environmental Quality (TCEQ) conducts up-to-date carcinogenic assessments for chemicals emitted in Texas. An inhalation unit risk factor (URF) was developed for ethylene dichloride (EDC, CAS 107-06-2) based on tumorigenicity results observed in a 2-year animal inhalation study conducted by Nagano et al. More specifically, the incidence of combined mammary gland tumors (adenomas, fibroadenomas, adenocarcinomas) in female rats demonstrated a statistically significant dose–response relationship, was amenable to benchmark concentration (BMC) modeling, was ultimately determined to be the most sensitive tumorigenic effect in the most sensitive species and sex, and was utilized as the carcinogenic endpoint for the development of the URF. The 95% lower confidence limit of the BMC at the 10% excess risk level (BMCL10 of 40.1 ppm) was determined for calculation of the URF. The resulting URF based on increased incidence of combined mammary gland tumors in female rats is 1.4E-02 per ppm (3.4E-03 per mg/m3). The lifetime air concentration corresponding to a no significant excess risk level of 1 in 100 000 is 0.71 ppb (2.9 μg/m3), which is considered sufficiently health-protective for use in protecting the general public against the potential carcinogenic effects of chronic exposure to EDC in ambient air.

Development of linear and threshold no significant risk levels for inhalation exposure to titanium dioxide using systematic review and mode of action considerations

Titanium dioxide (TiO2) has been characterized as a poorly soluble particulate (PSP) with low toxicity. It is well accepted that low toxicity PSPs such as TiO2 induce lung tumors in rats when deposition overwhelms particle clearance mechanisms. Despite the sensitivity of rats to PSPs and questionable relevance of PSP-induced tumors to humans, TiO2 is listed as a possible human carcinogen by some agencies and regulators. Thus, environmental toxicity criteria for TiO2 are needed for stakeholders to evaluate potential risks from environmental exposure and regulatory compliance. A systematic review of the literature was conducted to characterize the available data and identify candidate datasets upon which toxicity values could be derived. Key to this assessment, a survey of mechanistic data relevant for lung cancer was used to support quantitative inhalation risk assessment approaches. A total of 473 human studies were identified, 7 of which were epidemiological studies that met inclusion criteria to quantitatively characterize carcinogenic endpoints in humans. None of these studies supported derivation of toxicity criteria; therefore, animal data were used to derived safety values for TiO2 using different dose-metrics (regional deposited dose ratios, TiO2 particle surface area lung burden, and volumetric overload of alveolar macrophages), benchmark dose modeling, and different low-dose extrapolation approaches. Based on empirical evidence and mechanistic support for nonlinear mode of action involving particle overload, chronic inflammation and cell proliferation, a no significant risk level (NSRL) of 300 μg/day was derived. By comparison, low-dose linear extrapolation from tumor incidence in the rat lung resulted in an NSRL value of 44 μg/day. These toxicity values should be useful for stakeholders interested in assessing risks from environmental exposure to respirable TiO2.

In utero arsenic exposure in mice and early life susceptibility to cancer

In its review of the U.S. Environmental Protection Agency's toxicological review of inorganic arsenic (iAs), the National Academy of Sciences identified carcinogenic endpoints among the highest priority health effects of concern and stated the need to consider evidence that early life exposures may increase the risk of adverse health effects. Recent studies in mice suggest that in utero exposure to arsenic increases susceptibility to cancer later in life. These data are striking in light of the general lack of evidence for carcinogenicity in rodents exposed to iAs. To evaluate the transplacental carcinogenic potential of iAs, a detailed analysis of the toxicology literature evaluating the role of in utero arsenic exposure in carcinogenesis was conducted. Bladder, lung, and skin tumors, which are the tumor types most consistently reported in humans exposed to high arsenic levels, were not consistently increased in mouse studies. There was also a lack of concordance across studies for other tumor types not typically reported in humans. Therefore, we considered methodological and other critical issues that may have contributed to variable results and we suggest additional studies to address these issues. It was concluded that the available data do not provide evidence of a causal link between in utero arsenic exposure and cancer or indicate early life-stage susceptibility to arsenic-induced cancer, particularly at environmentally relevant doses.

Comparison of criteria used to access carcinogenicity in CPANN QSAR models versus the knowledge-based expert system Toxtree

The primary goal of this study was to describe and compare the criteria used to assess carcinogenic activity. The statistically-based predictive quantitative structure–activity relationship (QSAR) models based on the counter propagation artificial neural network (CPANN) algorithm, and knowledge-based expert systems based on a decision tree structural alert (SA) approach (Toxtree application), were considered. The integration of the QSAR (CPANN models) and SAR (Toxtree SA application) approach contributed to the mechanistic understanding of the QSAR model considered. The mapping technique inherent to CPANN Kohonen enables us to relate the similarities or dissimilarities within a congeneric set of chemicals with particular SAs for carcinogenicity. The focus of our investigations was the similarities and dissimilarities of the features used in the QSAR and SAR methods. Due to the complexity of the carcinogenic endpoint, the integration of different approaches allows the models to be improved and provides a valuable technique for evaluating the safety of chemicals.

Breast Cell Carcinogenesis Model for Intervention

Carcinogenesis is a multiyear, multistep, multipath disease process with progressive genetic and epigenetic alterations and associated tissue damage. More than 85% of breast cancers are sporadic and attributable to long-term exposure to small quantities of environmental carcinogenic substances. We have developed a chronically-induced cellular carcinogenesis model to mimic sporadic breast cancer development. This model allows us to identify carcinogenic substances, at physiologically-achievable low levels, capable of inducing breast cell carcinogenesis. With this model, we are able to identify cellular, biochemical, and molecular endpoints transiently and constitutively induced by single and cumulative exposures, respectively, thereby identifying carcinogenic substances involved in induction and progression of carcinogenesis. Using our model, we are also able to identify preventive agents effective in blocking these transient and constitutive carcinogenic endpoints. Thus, use of our model system will help accelerate development of novel strategies for targeted intervention of sporadic breast cancer in association with chronic exposure to low-dose carcinogenic substances, leading to a comprehensive reduction of breast cancer incidence and mortality.

A Mode-of-Action Approach for the Identification of Genotoxic Carcinogens

Distinguishing between clastogens and aneugens is vital in cancer risk assessment because the default assumption is that clastogens and aneugens have linear and non-linear dose-response curves, respectively. Any observed non-linearity must be supported by mode of action (MOA) analyses where biological mechanisms are linked with dose-response evaluations. For aneugens, the MOA has been well characterised as disruptors of mitotic machinery where chromosome loss via micronuclei (MN) formation is an accepted endpoint used in risk assessment. In this study we performed the cytokinesis-block micronucleus assay and immunofluorescence mitotic machinery visualisation in human lymphoblastoid (AHH-1) and Chinese Hamster fibroblast (V79) cell lines after treatment with the aneugen 17-β-oestradiol (E2). Results were compared to previously published data on bisphenol-A (BPA) and Rotenone data. Two concentration-response approaches (the threshold-[Td] and benchmark-dose [BMD] approaches) were applied to derive a point of departure (POD) for in vitro MN induction. BMDs were also derived from the most sensitive carcinogenic endpoint. Ranking comparisons of the PODs from the in vitro MN and the carcinogenicity studies demonstrated a link between these two endpoints for BPA, E2 and Rotenone. This analysis was extended to include 5 additional aneugens, 5 clastogens and 3 mutagens and further concentration and dose-response correlations were observed between PODs from the in vitro MN and carcinogenicity. This approach is promising and may be further extended to other genotoxic carcinogens, where MOA and quantitative information from the in vitro MN studies could be used in a quantitative manner to further inform cancer risk assessment.

Abstract 4801: Bronchoalveolar lavage fluid (BALF) from subchronic exposure to butylated-hydroxytoluene (BHT) inhibits gap junctional communication in a toll-like receptor 4-dependent manner.

Abstract Subchronic dosing of BHT in mice is a well-known model used to discretely study the tumor promotion stage of lung adenocarcinoma. Using this model, we have previously shown that functional toll-like receptor 4 (TLR4) is protective against inflammatory sequelae and primary tumor formation in the mouse lung. Gap junctional intercellular communication (GJIC) has been shown to regulate the signal transduction pathways of cells, and inhibition of this communication by toxicant exposure has been linked to dysregulation and eventual carcinogenic endpoints. As part of our research on the protective nature of TLR4 during tumor promotion, we utilized the BHT subchronic model (4 weekly i.p. doses of BHT) to examine the early effects on BALF in both BALB/c (BALB; Tlr4 sufficient) and C.C3H-Tlr4Lps-d mice (BALBLps-d-d; Tlr4 mutant). Analysis of the BALF 24 hours after the final dose for protein content and cytology was indicative of an inflammatory profile in all mice treated with BHT. Magnitude of response to BHT was highest in the BALBLps-d mice; the BALB appeared resistant. In an effort to further characterize the response of the pulmonary epithelium, the BALF samples were used to treat cultured C10 cells, a murine immortalized line derived from BALB/c alveolar type II cells, which are a precursor cell type for adenocarcinoma. Using the scrape-load dye transfer assay, a well-defined method to measure GJIC, we demonstrated marked inhibition of cellular communication after a 4 hour exposure to cell-free BALF that is both treatment and strain dependent. The direction and magnitude of effect is in parallel with that of the direct analysis of the BALF, i.e. we observed more inhibition in BALF from BALBLps-d compared to BALB mice. In addition, quantitative PCR (QPCR) analysis of C10 cells exposed to cell-free BALF for 24 hours indicates alterations in the transcription patterns in genes of innate immunity that are also treatment and strain dependent. These novel findings suggest endocrine signaling from the inflammatory milieu are complicit in the inhibition of GJIC during the promotion phase of carcinogenesis. Furthermore, these data establish a link between active gap junctions, tumor promotion, and the protective nature of TLR4 in an ex vivo model which will facilitate a mechanistic examination of these protective effects at the molecular level. Funded by ACS RSG-10-162-01-LIB (AKB). Citation Format: Thomas Hill, Carla-Maria Alexander, Alison K. Bauer. Bronchoalveolar lavage fluid (BALF) from subchronic exposure to butylated-hydroxytoluene (BHT) inhibits gap junctional communication in a toll-like receptor 4-dependent manner. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4801. doi:10.1158/1538-7445.AM2013-4801

First report on development of quantitative interspecies structure–carcinogenicity relationship models and exploring discriminatory features for rodent carcinogenicity of diverse organic chemicals using OECD guidelines

Different regulatory agencies in food and drug administration and environmental protection worldwide are employing quantitative structure–activity relationship (QSAR) models to fill the data gaps related with properties of chemicals affecting the environment and human health. Carcinogenicity is a toxicity endpoint of major concern in recent times. Interspecies toxicity correlations may provide a tool for estimating sensitivity towards toxic chemical exposure with known levels of uncertainty for a diversity of wildlife species. In this background, we have developed quantitative interspecies structure–carcinogenicity correlation models for rat and mouse [rodent species according to the Organization for Economic Cooperation and Development (OECD) guidelines] based on the carcinogenic potential of 166 organic chemicals with wide diversity of molecular structures, spanning a large number of chemical classes and biological mechanisms. All the developed models have been assessed according to the OECD principles for the validation of QSAR models. Consensus predictions for carcinogenicity of the individual compounds are presented here for any one species when the data for the other species are available. Informative illustrations of the contributing structural fragments of chemicals which are responsible for specific carcinogenicity endpoints are identified by the developed models. The models have also been used to predict mouse carcinogenicities of 247 organic chemicals (for which rat carcinogenicities are present) and rat carcinogenicities of 150 chemicals (for which mouse carcinogenicities are present). Discriminatory features for rat and mouse carcinogenicity values have also been explored.

Carcinogenic risk as the basis for fish advisories: A critique

Fish advisories are important tools in public health practice and are primarily used to translate fish contaminant levels into consumption recommendations for consumers. Even when a targeted advisory is issued, it may alter broad food consumption patterns among the public, including diminishing intake of fish-based protein and polyunsaturated fatty acids. Such alterations may have both positive (e.g., reduced exposure to contaminants) and negative (e.g., loss of health benefits or cultural traditions associated with consuming fish) consequences. Currently, a fish advisory may be based on the potential for either noncarcinogenic or carcinogenic endpoints. Consumption recommendations based on a cancer outcome are likely to be highly restrictive, potentially diminishing opportunities for the recognized health benefits associated with a fish-rich diet. This possibility causes us to raise 3 arguments against using cancer risk as the basis for fish consumption advisories. First, the benefits of fish consumption are widely recognized. Second, the standard methodology to predict cancer risk is likely to overestimate actual risk, often by orders of magnitude. Third, the public's real and perceived concerns about cancer may result in unintended consequences, such as avoidance of fish altogether. As an alternative to cancer-based advisories, we suggest that future advisories incorporate a multidisciplinary public health framework focused on avoiding noncarcinogenic health outcomes and encouraging the public to consume a balanced diet rich in fish. We also suggest that decision makers need to 1) understand which elements of the advisory process are science and which are implicit or default policy, 2) consciously consider whether these policy elements are appropriate for their particular situation, and 3) if not, be willing to make and defend alternative policy choices.

Nontargeted Multicomponent Analytical Screening of Plastic Food Contact Materials Using Fast Interpretation of Deliverables via Expert Structure-Activity Relationship Software

Plastic packaging materials may release compounds into packed foodstuffs. To identify potential migrants of toxicological concern, resins, and multilayer foils (mainly polyethylene) intended for the production of food contact materials were extracted and analyzed by GC/mass spectrometry. To identify even compounds of low concentrations, AMDIS software was used and data evaluation was safeguarded by the Kovats retention index (RI) system. In this way, 46 compounds were identified as possible migrants. The expert structure-activity relationship software DEREK for Windows was utilized to evaluate all identified substances in terms of carcinogenicity, genotoxicity, thyroid toxicity, and miscellaneous endpoints for humans. Additionally, a literature search for these compounds was performed with Sci-Finder, but relevant data were missing for 28 substances. Seven compounds with adverse toxicological effects were identified. In addition, the RIs of 24 commercial additive standards, measured with a GC capillary column of intermediate polarity, are given.