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Review Volume 121 | 2013
Human Health Effects of Trichloroethylene: Key Findings and Scientific Issues
Weihsueh A. Chiu,1 Jennifer Jinot,1 Cheryl Siegel Scott,1 Susan L. Makris,1 Glinda S. Cooper,1 Rebecca C. Dzubow,2 Ambuja S. Bale,1 Marina V. Evans,3 Kathryn Z. Guyton,1 Nagalakshmi Keshava,1 John C. Lipscomb,1 Stanley Barone Jr.,4 John F. Fox,1 Maureen R. Gwinn,1 John Schaum,5 and Jane C. Caldwell1
Background: In support of the Integrated Risk Information System (IRIS), the U.S. Environmental Protection Agency (EPA) completed a toxicological review of trichloroethylene (TCE) in September 2011, which was the result of an effort spanning > 20 years.
Objectives: We summarized the key findings and scientific issues regarding the human health effects of TCE in the U.S. EPA's toxicological review.
Methods: In this assessment we synthesized and characterized thousands of epidemiologic, experimental animal, and mechanistic studies, and addressed several key scientific issues through modeling of TCE toxicokinetics, meta-analyses of epidemiologic studies, and analyses of mechanistic data.
Discussion: Toxicokinetic modeling aided in characterizing the toxicological role of the complex metabolism and multiple metabolites of TCE. Meta-analyses of the epidemiologic data strongly supported the conclusions that TCE causes kidney cancer in humans and that TCE may also cause liver cancer and non-Hodgkin lymphoma. Mechanistic analyses support a key role for mutagenicity in TCE-induced kidney carcinogenicity. Recent evidence from studies in both humans and experimental animals point to the involvement of TCE exposure in autoimmune disease and hypersensitivity. Recent avian and in vitro mechanistic studies provided biological plausibility that TCE plays a role in developmental cardiac toxicity, the subject of substantial debate due to mixed results from epidemiologic and rodent studies.
Conclusions: TCE is carcinogenic to humans by all routes of exposure and poses a potential human health hazard for noncancer toxicity to the central nervous system, kidney, liver, immune system, male reproductive system, and the developing embryo/fetus.
Citation: Chiu WA, Jinot J, Scott CS, Makris SL, Cooper GS, Dzubow RC, Bale AS, Evans MV, Guyton KZ, Keshava N, Lipscomb JC, Barone S, Fox JF, Gwinn MR, Schaum J, Caldwell JC. 2013. Human Health Effects of Trichloroethylene: Key Findings and Scientific Issues. Environ Health Perspect 121:303–311; http://dx.doi.org/10.1289/ehp.1205879
Address correspondence to W.A. Chiu, National Center for Environmental Assessment (8601P), U.S. EPA, Two Potomac Yard (North Building), 2733 S. Crystal Dr., Arlington, VA 22202 USA. Telephone: (703) 347-8607. E-mail: email@example.com
This work has benefitted from advice and comments from a number of scientific reviewers—including members of the National Academies of Sciences, National Research Council panel on Trichloroethylene Health Risks, two U.S. EPA Science Advisory Board review panels, and scientists at federal agencies (including the U.S. EPA)—as well as from others who prepared public comments. We also thank P. Anastas, R. Clark, P. Preuss, D. Bussard, V. Cogliano, B. Sonawane, and P. White for providing U.S. EPA management support.
The views expressed in this article are those of the authors and do not necessarily represent the views or policies of the U.S. EPA.
The authors declare they have no actual or potential competing financial interests.
Received: 10 August 2012
Accepted: 17 December 2012
Advance Publication: 18 December 2012
Final Publication: 1 March 2013
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Trichloroethylene (TCE) is a chlorinated solvent once widely used as a metal degreaser, chemical intermediate and extractant, and component of some consumer products. Total releases to the environment reported to the U.S. Environmental Protection Agency (EPA) Toxics Release Inventory have declined from > 57 million pounds in 1988 to about 2.4 million pounds in 2010 (U.S. EPA 2012b). Because it has a relatively short half-life, TCE is not commonly detected in biomonitoring surveys, and the percentage of subjects with detectable levels (> 0.1 ng/mL) has declined from about 10% to 1% between samples collected in 1988–1994 and those collected in 2003–2004 (Centers for Disease Control and Prevention 2009; Wu and Schaum 2000]. From a regulatory and environmental-cleanup perspective, TCE has been identified in soil or groundwater at > 700 of approximately 1,300 Superfund hazardous waste sites listed by the U.S. EPA (2011c). Additionally, the U.S. EPA has identified TCE as one of the volatile organic compounds to be regulated as a group in drinking water (U.S. EPA 2010, 2011a) and as one of the priority existing chemicals under review for regulatory action under the Toxic Substances Control Act (U.S. EPA 2012a). Indeed, because of TCE's continued presence in the environment, most people are likely to have some exposure to the compound through contaminated drinking water, ambient outdoor or indoor air, or, less commonly, contaminated foods.
The U.S. EPA's Integrated Risk Information System (IRIS) program released an updated human health risk assessment of TCE in September 2011 (U.S. EPA 2011d). This assessment was developed over a period of > 20 years and underwent many stages of both internal and external peer review. Key inputs were recommendations for additional analysis and research from a National Research Council (NRC) panel report reviewing the key scientific issues pertaining to TCE hazard and dose–response assessment (NRC 2006). This report, together with a series of issue papers developed by U.S. EPA scientists (Caldwell and Keshava 2006; Chiu et al. 2006a, 2006b; Keshava and Caldwell 2006; Scott and Chiu 2006), provided the foundation for developing an objective, scientifically rigorous human health risk assessment for TCE. The U.S. EPA's final assessment also incorporated input from two independent peer reviews by the U.S. EPA's Science Advisory Board (U.S. EPA SAB 2002, 2011), other federal agencies (U.S. EPA 2009b, 2011b), and the public (U.S. EPA 2009a).
Here we describe key findings and scientific issues addressed in the U.S. EPA's toxicological review of TCE (U.S. EPA 2011d), covering the following topics: a) the role of metabolism in TCE toxicity, which was informed by the development and use of an updated physiologically based pharmacokinetic (PBPK) model; b) the carcinogenicity of TCE, including the development of meta-analyses of epidemiologic studies for informing causal inferences, as recommended by the NRC (2006), and analyses of laboratory animal mechanistic and toxicokinetic data contributing to the evaluation of biological plausibility of the epidemiologic data; and c) noncancer toxicity related to two end points—immunotoxicity and developmental cardiac toxicity—for which substantial new data have become available. Findings and issues related to other important topics not discussed here (e.g., susceptibility, mixtures/coexposures, and dose–response assessment) have been described previously (e.g., Caldwell JC et al. 2008; NRC 2006; U.S. EPA 2011d).
Role of Metabolism in TCE Toxicity
A broad and complex range of relevant information for assessing human health effects of TCE is available. Previous reviews have found TCE to adversely affect the central nervous system (Bale et al. 2011), liver (Bull 2000), kidney (Lash et al. 2000b), immune system (Cooper et al. 2009), and reproductive systems and developing embryo/fetus (NRC 2006). As shown in Figure 1, TCE is metabolized in humans and experimental animal species by both oxidation and glutathione (GSH)-conjugation metabolic pathways, with subsequent production of numerous toxicologically active compounds (Chiu et al. 2006b; Lash et al. 2000a). These include the oxidative metabolites chloral hydrate, trichloroacetic acid (TCA), and dichloroacetic acid, and the GSH conjugation metabolites dichlorovinyl glutathione and dichlorovinyl cysteine. This complex assortment of metabolic compounds is generated from and transported across multiple tissues, making evaluation of mechanistic data especially challenging (Caldwell JC et al. 2008). Liver effects of TCE are thought to result from oxidative metabolites (Buben and O'Flaherty 1985; Bull 2000), whereas effects on kidney are generally associated with metabolites resulting from GSH conjugation (Lash et al. 2000b). The identity of TCE metabolites involved in the induction of other health effects of TCE is less clear, although similarities have been observed between TCE and its oxidative metabolites in the respiratory tract (e.g., Odum et al. 1992) and developmental toxicity (e.g., Johnson et al. 1998a).
Figure 1 – Simplified TCE metabolism scheme. Metabolism of TCE occurs through two main irreversible pathways: oxidation via the microsomal mixed-function oxidase system (i.e., cytochrome P450s; left) and conjugation with GSH by glutathione S-transferases (GSTs; right). Oxidation occurs predominantly in the liver, and to a lesser extent in the lung; the first metabolic products are TCE-oxide (TCE‑O), chloral (CHL), and chloral hydrate (CH), with the latter two quickly transformed to trichloroethanol (TCOH; a reversible reaction) and trichloroacetic acid (TCA). TCOH is glucuronidated to form TCOH-glucuronide (TCOG), which undergoes enterohepatic recirculation (excretion in bile with regeneration and reabsorption of TCOH from the gut). TCA and TCOG are excreted in urine. Further metabolism of TCA and TCOH has not been well characterized but may include dichloroacetic acid (DCA) (Lash et al. 2000a). TCE-O may also form DCA, among other species (Cai and Guengerich 1999). TCE conjugation with GSH in the liver or kidney form dichlorovinyl glutathione (DCVG), which is further processed in the kidney, forming the cysteine conjugate S-dichlorovinyl-L-cysteine (DCVC). DCVC may be bioactivated by beta-lyase or flavin-containing monooxygenases to reactive species (Anders et al. 1988; Krause et al. 2003; Lash et al. 2003), or (reversibly) undergo N-acetylation to the mercapturate N-acetyl dichlorovinyl cysteine (NAcDCVC), which is then excreted in urine or sulfoxidated by CYP3A to reactive species (Bernauer et al. 1996; Birner et al. 1993; Werner et al. 1995a, 1995b).
aMetabolites identified in blood or urine following in vivo TCE exposure (rodent or human).
Tools such as PBPK models can be very useful for integrating complex toxicokinetic information on absorption, distribution, metabolism, and excretion of TCE and its metabolites. Many PBPK models for TCE have been developed to predict the relationship between external measures of exposure and internal dose measures (Bois 2000a, 2000b; Clewell et al. 2000; Fisher 2000; Hack et al. 2006). Chiu et al. (2009) and Evans et al. (2009) updated and "harmonized" these efforts into a new model for use in the IRIS assessment.
For example, Evans et al. (2009) and Chiu (2011) illustrated the importance of internal dose in investigating mechanisms of TCE toxicity, addressing the key question of whether the TCE metabolite TCA can account for mouse hepatomegaly caused by TCE. They used the TCE PBPK model to compare the hepatomegaly response after TCE administration with the response after direct administration of its metabolite TCA, using the common internal dose measure of TCA liver concentration. If TCA were the only contributor to TCE-induced hepatomegaly, this comparison would show equal changes in liver weight for equal TCA liver concentrations, regardless of whether TCA was the result of TCE metabolism or the result of direct TCA administration. However, as reported by Evans et al. (2009) and Chiu (2011), TCA appears to account for no more than half of the hepatomegaly that resulted from TCE exposure, implying that effects related to TCE exposure beyond those accounted for by TCA are also operative in TCE-induced hepatomegaly.
Evaluation of cancer epidemiology for kidney cancer, liver cancer, and non-Hodgkin lymphoma (NHL). The U.S. EPA conducted a systematic review of 76 human epidemiologic studies on TCE and cancer (Scott and Jinot 2011; U.S. EPA 2011d). Each study was evaluated with respect to explicitly identified characteristics of epidemiologic design and analysis to examine whether chance, bias, or confounding could be alternative explanations for the study's results. A more in-depth analysis (including meta-analysis) of the epidemiologic studies was conducted for kidney cancer, liver cancer, and NHL. These end points were of a priori interest based on the results of a preliminary review of the epidemiologic data and the findings from rodent bioassays of TCE exposure.
Meta-analysis approach and results. Meta-analyses can be used to combine underpowered studies, to evaluate effects across the set of studies, and to examine consistency (or heterogeneity) of results. The NRC (2006) identified a number of weaknesses in previous meta-analyses of TCE carcinogenicity, such as subjective assessment of quality and lack of sensitivity analyses. Thus, the U.S. EPA conducted new meta-analyses to support evaluation of the epidemiologic data on TCE (Scott and Jinot 2011; U.S. EPA 2011d). As recommended by the NRC (2006), the U.S. EPA (2011d) a) established objective study inclusion criteria; b) fit the data to both fixed-effect and random-effects models; c) evaluated statistical heterogeneity across the studies; d) performed sensitivity analyses examining the influence of individual studies and of different measures of relative risk (RR) from studies presenting alternative estimates (e.g., incidence or mortality); and e) conducted tests for potential publication bias (which may occur if positive studies are more likely to be published). Figure 2 presents the meta-analysis summary effect estimates (RRm) from the random-effects models for any TCE exposure (Figure 2A) and for the highest TCE exposure groups (Figure 2B).
Figure 2 – Forest plots from random-effects models of overall (i.e., "ever" or "any") TCE exposure (A) and highest TCE exposure groups (B), adapted from Scott and Jinot (2011). Individual study RR (squares) and RRm (diamonds) values are plotted with 95% CIs (LCL, lower confidence limit; UCL, upper confidence limit) for each cancer type. Symbol sizes reflect relative weight of the studies.
Issues in the interpretation of cancer epidemiologic evidence. Two additional key issues regarding the U.S. EPA's interpretation (U.S. EPA 2011d) of the cancer epidemiologic evidence for kidney cancer, NHL, and liver cancer have been raised in peer review and public comments: the modest magnitude of the RRm estimates for the three cancer types, and the role of meta-analysis within a causality determination.
The RRm estimates from the U.S. EPA (2011d) meta-analyses for the three cancer types were modest {e.g., with overall exposure (Figure 2A): 1.27 [95% confidence interval (CI): 1.13, 1.43] for kidney cancer; 1.23 (95% CI: 1.07, 1.42) for NHL, and 1.29 (95% CI: 1.07, 1.56) for liver cancer (Scott and Jinot 2011)}, raising the possibility that the observed associations could be the result of confounding. However, a detailed examination by the U.S. EPA of potential confounding from lifestyle factors or other occupational exposures concluded that confounding was not supported as an alternative explanation for the observed excesses (U.S. EPA 2011d).
For example, although smoking can potentially confound kidney cancer results, several kidney cancer case–control studies included in the meta-analysis (U.S. EPA 2011d) reported associations with TCE exposure even after controlling for smoking in statistical analyses. In addition, if the cohort studies had been confounded by smoking, increased lung cancer risk would be expected. However, increases in lung cancer risk in individual studies were either absent or insufficient to account for the observed excess kidney cancer risk. Overall, after combining studies, RRm estimates for lung cancer were 0.96 (95% CI: 0.76, 1.21) for overall TCE exposure and 0.96 (95% CI: 0.72, 1.27) for the highest exposure groups (Scott and Jinot 2011; U.S. EPA 2011d).
Another key issue is the role of meta-analysis in the overall evaluation of causality. Meta-analysis can provide an objective, quantitative method to increase statistical power and precision because the resultant summary effect estimate is based on multiple studies. Strengths of the meta-analyses (U.S. EPA 2011d) include study identification based on a systematic and transparent review, evaluations of potential publication bias, examinations of the sensitivity of the overall effect to different inputs, and investigations of possible factors responsible for any statistical heterogeneity observed across studies. However, the U.S. EPA's characterization of the epidemiologic evidence (U.S. EPA 2011d) considered multiple aspects of the data as a whole and did not rely solely on the meta-analysis findings.
Synthesis of epidemiologic evidence. Table 1 summarizes the epidemiologic evidence according to the key concepts proposed by Hill (1965). For TCE and kidney cancer, there was convincing evidence of a causal association in humans. Particularly compelling was the consistency of increased RR estimates for kidney cancer across the 15 independent epidemiologic studies of different designs and populations from different countries that met the criteria for inclusion in the meta-analysis (Figure 2). The U.S. EPA (2011d) observed increased RRm estimates for kidney cancer that were robust, not being sensitive to different study or RR inputs. The U.S. EPA (2011d) also found no evidence of heterogeneity among studies or publication bias. The observations of a greater RRm estimate with the highest exposure groups (Figure 2B) and of statistically significant trends between TCE exposure and kidney cancer in two high-quality epidemiologic studies (Charbotel et al. 2006; Moore et al. 2010) support an exposure–response gradient. Finally, potential confounding from smoking or other occupational exposures was unlikely to explain the association of TCE exposure with kidney cancer.
Table 1 – Primary components for a causality determination based on the epidemiologic database for TCE.
The evidence on carcinogenicity from epidemiologic studies of TCE exposure was strong for NHL, although less convincing than for kidney cancer (U.S. EPA 2011d). Of the 17 studies that met the criteria for meta-analysis inclusion, most observed increased RR estimates (Figure 2A). The increased RRm estimate observed in the meta-analysis of NHL and overall TCE exposure was robust because it was not sensitive to different study or RR inputs. However, some heterogeneity among studies was observed, although it was not statistically significant. There was also some evidence of potential publication bias. An exposure–response gradient is supported by observations of a greater RRm estimate with the highest exposure groups (Figure 2B) and of a statistically significant trend between TCE exposure and NHL in a high-quality epidemiologic study (Purdue et al. 2011).
The epidemiologic evidence was more limited for liver cancer, where only cohort studies with small numbers of cases were available (U.S. EPA 2011d). Of the nine studies that met the criteria for meta-analysis inclusion, most reported increased RR estimates (Figure 2A). The U.S. EPA (2011d) observed a statistically significantly increased RRm estimate in their meta-analysis of liver cancer and overall TCE exposure, but the statistical significance depended on the large study by Raaschou-Nielsen et al. (2003). There was no evidence of heterogeneity or publication bias. However, the data available did not support an exposure–response gradient because the RRm estimate for the highest exposure groups was lower than that for overall exposure (Figure 2B) and because none of the available studies reported a statistically significant trend between TCE exposure and liver cancer.
Experimental animal studies, analysis of mode of action, and toxicokinetic considerations. There is clear evidence of TCE carcinogenicity in rodents. Particularly notable is the site-concordant finding of TCE-induced kidney tumors in multiple strains and both sexes of rats exposed by inhalation or gavage [Maltoni et al. 1986; National Toxicology Program (NTP) 1988, 1990]. Although the increased incidences were low, they were sometimes statistically significant and were considered biologically significant in light of the very low historical incidences of renal tumors in control rats in various laboratories. There is also site concordance for liver tumors, which were reported in both Swiss and B6C3F1 mice (strains with lower and higher background rates of this tumor, respectively), and in both sexes in the latter strain (Maltoni et al. 1986; National Cancer Institute 1976; NTP 1990). The evidence was more limited for TCE-induced lymphohematopoietic cancers in rats and mice (Henschler et al. 1980; Maltoni et al. 1986; NTP 1988, 1990). TCE inhalation bioassays have demonstrated a statistically significant increase in pulmonary tumors in mice (Fukuda et al. 1983; Maltoni et al. 1986) but not other species [i.e., rats and hamsters (Fukuda et al. 1983; Henschler et al. 1980; Maltoni et al. 1986)]. Finally, testicular (interstitial cell and Leydig cell) tumors were significantly increased in Sprague-Dawley rats exposed via inhalation (Maltoni et al. 1986) and Marshall rats exposed via gavage (NTP 1988). In three other tested rat strains, ACI, August, and F344/N, a high (> 75%) control rate of testicular tumors limited the ability to detect a treatment effect, although a positive trend was reported in ACI rats (NTP 1988, 1990). Overall, the rodent cancer data add substantial biological plausibility for TCE carcinogenicity in humans, particularly when combined with the mechanistic data findings.
Table 2 summarizes hypothesized modes of action and mechanistic data informative to the evaluation of TCE's carcinogenic mode of action for liver, kidney, and other tumors. Mode-of-action analyses can inform judgments regarding the human relevance of animal bioassay results and aid in identifying particularly susceptible populations or life stages (U.S. EPA 2005). For kidney carcinogenicity, the U.S. EPA (2011d) concluded that a mutagenic mode of action is operative for TCE, providing further biological plausibility for the epidemiologic findings of TCE-induced kidney cancer. The identification of the mutagenic metabolites as being derived from the GSH conjugation pathway further suggests increased susceptibility in populations with greater metabolism through this pathway. Consistent with this hypothesis, Moore et al. (2010) found a statistically significant association among TCE-exposed persons with an active GSTT1 (glutathione-S-transferase theta-1) enzyme [odds ratio (OR) = 1.88; 95% CI: 1.06, 3.33], but not among those with no GSTT1 activity (OR = 0.93; 95% CI: 0.35, 2.44). Although data are lacking on early-life susceptibility to TCE carcinogenicity, the analysis by Barton et al. (2005) suggested increased susceptibility to cancer from early-life exposures, particularly for chemicals acting through a mutagenic mode of action. For other end points, there are inadequate data to support a particular hypothesized mode of action.
Table 2 – Selected key mode-of-action hypotheses and support.
The evaluation of TCE carcinogenicity (U.S. EPA 2011d) also considered toxicokinetic data on TCE and metabolites, which are consistent with qualitatively similar absorption, distribution, metabolism, and excretion across species and routes of exposure (Lash et al. 2000a). Mice, rats, and humans all metabolize TCE via the pathways illustrated in Figure 1. Thus, toxicokinetic data support the biological plausibility of TCE carcinogenicity in humans because humans and experimental animals have similar mixtures of TCE and metabolites in target tissues.
Another issue informed by toxicokinetic data is whether TCE carcinogenicity depends on route of exposure, given that the vast majority of the available epidemiologic data are from inhalation exposures to TCE. Because TCE is systemically distributed and undergoes systemic metabolism from all routes of exposure, there is no reason to expect that cancers such as kidney cancer, NHL, or liver cancer, which originate in separate tissues, would be dependent on route of exposure. Also, TCE-induced tumors have been reported in rodents by both the oral and inhalation routes (Maltoni et al. 1986; NTP 1988, 1990). Therefore, conclusions regarding TCE carcinogenicity would apply equally to any exposure route.
Conclusions as to carcinogenic hazard. Supported by the analyses described above and following the U.S. EPA's Guidelines for Carcinogen Risk Assessment (U.S. EPA 2005), TCE is characterized as "carcinogenic to humans" by all routes of exposure (U.S. EPA 2011d). This conclusion was based primarily on convincing evidence of a causal association between TCE exposure and kidney cancer in humans. The epidemiologic evidence is strong for NHL, although less convincing than for kidney cancer. Issues increasing the uncertainty in the NHL association include study heterogeneity, potential publication bias, and less evidence for an exposure–response gradient. The epidemiologic evidence was more limited for liver cancer, where only cohort studies with small numbers of cases were available. Finally, animal bioassay, mechanistic, and toxicokinetic data provide further corroboration and biological plausibility to the epidemiologic findings, thus supporting a causal link between TCE exposure and cancer (Table 1).
Noncancer Toxicity
As part of its evaluation of TCE noncancer toxicity, the U.S. EPA analyzed the available experimental animal, human epidemiologic, and mechanistic studies of TCE. A summary of the relevant studies for each end point is available in Supplemental Material, Table S1 (http://dx.doi.org/10.1289/ehp.1205879). Below we discuss the data pertaining to immunotoxicity and developmental cardiac toxicity, for which there are substantial new experimental and epidemiologic studies (U.S. EPA 2011d), and about which scientific issues have been raised by reviewers or comments. We also provide an overall summary of the hazard conclusions for noncancer toxicity.
Immunotoxicity. As recently reviewed by Cooper et al. (2009) and documented in the TCE assessment (U.S. EPA 2011d), the human and laboratory animal studies of TCE and immune-related effects provide strong evidence that TCE exposure increases the risk of autoimmune disease and a specific type of generalized hypersensitivity syndrome. In addition to the epidemiologic studies of specific diseases (e.g., systemic sclerosis), changes in cytokine levels reflecting an inflammatory immune response have been reported in relation to TCE exposure in occupational (Iavicoli et al. 2005) and residential (i.e., infants exposed to TCE in indoor air) (Lehmann et al. 2001, 2002) settings. Also, many case reports have associated a severe hypersensitivity skin disorder, distinct from contact dermatitis and often accompanied by hepatitis, with occupational TCE exposure, with prevalences as high as 13% of workers in the same location (Kamijima et al. 2007, 2008).
Human evidence for autoimmune-related effects is supported by experimental animal studies. Numerous studies have demonstrated TCE-induced progressive, accelerated autoimmune responses in autoimmune-prone mice (reviewed by Cooper et al. 2009). After shorter exposure periods, changes in cytokine levels appear similar to those reported in human studies. Longer exposure periods led to more severe effects, including autoimmune hepatitis, inflammatory skin lesions, and alopecia, that differ from the "normal" expression of autoimmune effects in these mice. TCE-induced autoimmune effects have also been reported in B6C3F1 mice, which are not known to have any particular immune-related susceptibility (Gilkeson et al. 2004; Peden-Adams et al. 2006). A treatment-related increase in delayed hypersensitivity response accompanied by hepatic damage has been observed in guinea pigs following intradermal TCE injection (Tang et al. 2002, 2008), and increased hypersensitivity response was reported in mice exposed via drinking water prenatally and postnatally (gestation day 0 through to 8 weeks of age) (Peden-Adams et al. 2006).
There is less evidence regarding a possible role of TCE exposure in immunosuppression. Immunosuppressive effects have been reported in a number of experimental studies in mice and rats [see Supplemental Material, Table S1 (http://dx.doi.org/10.1289/ehp.1205879)]. Reported effects include reduced responses to bacterial challenge in mice (Aranyi et al. 1986; Selgrade and Gilmour 2010) and decreased numbers of antibody-forming cells in rats and developmentally exposed mice (Peden-Adams et al. 2006; Woolhiser et al. 2006).
Overall, the concordance of human and laboratory animal studies and the spectrum of effects (from biomarkers to frank expressions of disease) strongly support the conclusion that TCE causes immunotoxicity, particularly in the form of autoimmune disease and a specific type of severe hypersensitivity skin disorder, with more limited evidence for immunosuppression. Moreover, these findings lend additional biological plausibility to the association between TCE and NHL, as alterations in immune status are associated with increased risk of NHL (Grulich et al. 2007).
Developmental cardiac toxicity. The TCE data include a number of epidemiologic and animal toxicity studies that indicate TCE-induced developmental toxicity. Congenital malformations, particularly cardiac defects, have been associated with exposures to TCE and/or its metabolites in both humans and experimental animals [for example studies, see Supplemental Material, Table S1 (http://dx.doi.org/10.1289/ehp.1205879)]. Other TCE-related developmental outcomes observed in both humans and experimental animals include embryonic or fetal mortality, prenatal growth inhibition, and neurological and immunological functional deficits. (see Supplemental Material, Table S1).
As noted by the NRC (2006), the cardiac teratogenicity of TCE has been the focus of considerable study and analysis (Bove et al. 2002; Hardin et al. 2005; Johnson et al. 1998b; Watson et al. 2006). Only geography-based epidemiology studies have evaluated whether there is an association between maternal TCE exposure and cardiac defects in offspring [see Supplemental Material, Table S1 (http://dx.doi.org/10.1289/ehp.1205879)], with some of the studies reporting statistically significant elevations in a variety of cardiac defects [Agency for Toxic Substances and Disease Registry (ATSDR) 2006, 2008; Yauck et al. 2004], and others reporting nonstatistically significant elevations in risk (Bove 1996; Bove et al. 1995; Goldberg et al. 1990). Interpretation of these data has been controversial because many of the studies are limited by small numbers of cases, insufficient exposure characterization, chemical coexposures, and other methodological deficiencies. In addition, these studies aggregate a broad array of TCE-associated cardiac malformations and have inadequate statistical power to identify any particular kind(s) of defect that may be more susceptible to induction by TCE. The NRC (2006) noted that the epidemiologic studies—although limited individually—as a whole showed relatively consistent elevations for cardiac malformations with similar relative effect sizes of 2- to 3-fold, some of which were statistically significant, associated with TCE exposure across multiple studies.
The outcomes of studies in rodents exposed to TCE during gestation show an inconsistent pattern. Some studies identified significant treatment-related increases in the overall incidence of cardiac anomalies at environmentally relevant exposure levels (e.g., Johnson et al. 2003, 2005), whereas others reported no excess cardiac abnormalities at much higher dose levels (e.g., Carney et al. 2006; Fisher et al. 2001). Several methodological factors may contribute to differences across study outcomes, such as the route of administration, test substance purity, test species or strain, timing of dosing or fetal evaluation, procedures used in dissecting and examining fetal hearts, statistical approaches applied to data evaluation, and generally uncharacterized interlaboratory variation.
Other available data providing evidence of TCE cardiac teratogenicity come from avian and in vitro mechanistic studies (NRC 2006). For instance, studies in chick embryos reported consistent effects on cardiogenesis (many demonstrating septal and valvular alterations) when TCE was administered during critical stages of heart development (Drake et al. 2006a, 2006b; Loeber et al. 1988; Rufer et al. 2010); these findings are similar to some of the cardiac defects observed in rodent studies following in utero TCE exposures (Johnson et al. 2003). The events of cardiac morphogenesis in birds and mammals are similar; both involving mesenchymal cells that form endocardial cushion tissue with subsequent differentiation into septa and valvular structures in the adult heart (NRC 2006). Thus, cultured embryonic chick atrioventricular canal cushion cells have been used to examine chemically induced disruptions in cardiac morphogenesis. In this model, TCE inhibited endothelial separations and mesenchymal cell formation (Boyer et al. 2000; Mishima et al. 2006) or adhesive properties of endocardial cells (Hoffman et al. 2004), either of which could potentially result in septal or valvular malformations. Other TCE-induced effects that may have morphologic consequences in the developing heart include disruption of endothelial oxide synthetase, which has a role in endothelial cell proliferation (Ou et al. 2003), and interference with proteins involved in intercellular Ca2+ regulation, which may result in altered blood flow (Caldwell PT et al. 2008, 2010; Collier et al. 2003; Selmin et al. 2008).
Overall, the avian and in vitro data substantially increase the biological plausibility for TCE-induced cardiac teratogenesis, and thus strongly support the more limited epidemiologic and in vivo rodent data suggesting that TCE induces cardiac teratogenicity. Moreover, mechanistic data support the possibility that multiple modes of action with different targets within the developing heart may be operant in eliciting cardiac malformations, consistent with the reported association between TCE and overall cardiac malformations in the absence of a strong association with any particular type of defect.
Conclusions as to noncancer hazard. Table 3 summarizes the evidence for TCE noncancer toxicity across target organs and systems (for additional details, see U.S. EPA 2011d). In addition to the immunotoxicity and developmental cardiac toxicity discussed above, there is strong evidence for TCE-induced neurotoxicity, kidney toxicity, liver toxicity, male reproductive toxicity, and several developmental effects in addition to cardiac toxicity. More limited evidence exists for the toxicity of TCE in the respiratory tract and female reproductive system.
Table 3 – Key conclusions for TCE noncancer toxicity.
TCE is carcinogenic to humans by all routes of exposure and poses a potential human health hazard for noncancer toxicity to the central nervous system, kidney, liver, immune system, male reproductive system, and the developing embryo/fetus. These conclusions are based on analyses of a broad spectrum of information from thousands of scientific studies and input from numerous scientific reviews. In the last decade, substantial new scientific data on the human health effects of TCE have become available. Moreover, methodologic advancements—such as modeling of TCE toxicokinetics, meta-analyses of epidemiologic studies, and analyses of mechanistic and noncancer hazard information—have improved the scientific rigor and transparency of data interpretation. The approaches and conclusions of the U.S. EPA's analyses (U.S. EPA 2011d) are consistent with the recommendations of the NRC (2006) and were affirmed by independent peer review through the U.S. EPA's Science Advisory Board (U.S. EPA SAB 2011). In addition, the International Agency for Research on Cancer (IARC) recently upgraded its carcinogenicity classification of TCE to "carcinogenic to humans" (Guha et al. 2012). Finally, studies on the health effects of TCE continue to report findings similar to those described in the U.S. EPA's assessment, such as kidney carcinogenicity and toxicity (Karami et al. 2012; Vermeulen et al. 2012), immunotoxicity (Hosgood et al. 2011), and developmental cardiac toxicity (Forand et al. 2012).
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The Advisers Programme quickly became an established part of YPFP's activities in Brussels. We have organised three cycles so far and are excited to launch the next (fourth) one in the coming days.
YPFP created an incredible network of young professionals over the five years of its presence in Brussels. Sharing those contacts with our members through the Advisers Programme is a natural way of fulfilling part of YPFP's mission - to provide future leaders with the network they need to better face critical challenges.
The third cycle saw 34 participants joining the Programme. "We connected 17 young and dedicated professionals to more senior peers." informs Erik Zolcer, the Programme's coordinator. "We try to make sure the people do not know each other from before, so they gain a new contact," explains Erik.
YPFP Brussels members can apply for both roles: as Advisees and as Advisers too. "We give our experienced members the opportunity to share tips on getting ahead and 'send the elevator back down', so to speak". "Lots of thought goes into pairing. We want to make sure people really are an asset to each other," adds Erik.
Besides connecting people, participants get an exclusive access to a set of career development seminars. During the third cycle, YPFP hosted dedicated Advisers Programme workshops on: CV writing, professional business writing, public speaking and networking. Besides fine-tuning crucial skills, the workshops give both partners ideas on what to discuss in their one-to-one sessions. "We will definitely keep on bringing in career development experts to the fourth cycle as well," reveals Erik. "We will hold a session on discovering one's core strengths, but we will visit the ever-green topic of getting ahead in the EPSO competition too. And much more."
Most participants appreciate the personal touch. Advisers are accomplished professionals and dedicate time to address the Advisee's issues. For instance, one Advisee wanted to get a job in public affairs. Her Adviser – a director level public affairs professional –offered mock interviews on camera. To make the experience more real, this took place at the Adviser's office. "I was pleased to learn how creative and devoted some of the Advisers are", shares Erik. "We appreciate their input and applaud their enthusiasm."
If you are interested in getting involved, visit our dedicated YPFP Advisers Programme web page and learn more.
The opinions expressed in this article are the author's own and do not reflect the views of their employer or Young Professionals in Foreign Policy.


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Applying gradients to the text:
So after you have something that you are happy with, it is time to move onto something a little more complicated and that is adding a gradient over the text you have created to make everything more sleek and professional looking. This particular effect took me a long time to figure out but is really simple to master and the use well. So, with what we have already created selected, hit control + shift + n and it will give us a new layer above our text. I want you then to hit G and it should select the gradient tool. It may be hidden under the pain bucket tool though and if it is, you will have to go and get it yourself. With the gradient tool selected though, the work can begin.
What we are going to do first in double-click on what I have illustrated for you to bring up the gradient options:
Once you have done this, you should be met with this dialogue box (minus the red rings):
The bigger red ring indicates how many different stops you are going to have as your colour changes. I like to use three a lot and will be using it for this example. However, please not that as you get further along to the right of the row and onto the second row, more stops become available, allowing you to add more stops and ultimately, more colour to the gradient you are creating. Now, if you are following along with me, select the gradient I have chosen and now concentrate on the smaller rings at the bottom. These rings indicate the stops and the colours that you will use. Double-click on the one to the far left and this box will be brought up:
I am choosing another lovely pin colour and hitting OK once I am happy with the result. Notice how it shows how the colour is changing. So, go ahead and pick two more colours that you are happy with and hit enter.
What you will have now, is an empty layer above the layer with your text on it. Go to your canvas and draw a line horizontally across it. It can be any length and it should give you your desired colours predominantly on top of everything else. It should look something like this:
Please not that I have switched the colours around by drawing the line from right to left and not left to right. You can also do this to the same end by drawing up to down instead of down to up. Either way, you should end up with something similar to that which is shown above. The next part is the only tricky part. Hold Control + Alt and hover over the line between the gradient layer and the text layer. Unfortunately, I cant show you this step because a screen shot filters out the mouse. It will have a little padlock sign though and once you have that between the two, left click and it will lock the two layers together, giving you this:
Im pretty sure that is what is called a clipping mask with a gradient and it can also be done using an image, if you so prefer. Instead of putting the gradient on the new layer, try putting an image on there and following the same padlocking technique and it will give you a similar result in the end.
Mission accomplished.
Thanks for reading, folks and happy sigging!
OK, so having been requested to do a signature tutorial on my Randy Orton sig that I am sporting at the time of writing this, I will attempt to recreate the steps I took to get this effect and show you how, with a little effort and experimentation, you can make something like this:
SO, what is pictured above is the desired effect that we want and I will try my best to come up with the same thing as is pictured. However, I don't it saved as a PNG so some of the steps may be a little different but that is the strength of Photoshop and digital arts in general. So, without further ado, let us get on with trying to recreate something like what is pictured. This time, however, I will be using Triple H as a subject and will hopefully have similar results. Right now, I don't imagine there will be any problems with that though.
Creating the Sig:
Now, the first thing you want to do is open a canvas that is 396 pixels by 196 pixels. After you have done this, makes sure that the canvas is black and also make sure that you have downloaded the sparkle brushes that can be found in a past tutorial. Once you have those, you are ready to start. Take out some sparkle brushes and make your foreground colour white and go to work painting on some sparkles. Once you have done that, you should have something that looks like this:
However, I will stress that this is not a necessity. I do like this though because the sparkle brushes work really well with colour overlays when we get there. So, what is above should be used as a guideline only and please feel free to do what you want and experiment a little to get the effects that you see in your head. That goes for all of the steps that I am covering. Try and experiment and you will have a wonderful grasp of what looks great and what doesn't. So once, you have something like that, you will need to import the first picture that you are going to use. Generally, I go with what is going to be "untorn", so to speak. I will be using a Triple H render from PSD dreams for all of the images and those will be listed.
The first render can be found here:
So once, you have that, import the render onto your canvas and position it at the top of the page. Be careful to plan out what you are trying to achieve when you do this and ensure that you are future proofing your sig, By that, I mean that you are leaving enough room for later steps and ensuring that nothing will be in the way when we get there. So, once I did this, I had something that looked like this:
Please notice that I have left enough space on both the left and right of the render to make the rest of the future content have enough space to flow. Once you have this though, you are ready to continue. I am going to be using a green colour scheme for the Triple H sig as opposed to the red of the Randy Orton sig. Feel free to use whatever colour you want though. Now, what you want to do is hit "control + J" to duplicate the layer and then take out a soft edged brush of around 45 pixels and paint over Triple H. This will give you something that looks like this:
Now, what you want to do is smudge that around a little and you should come up with something that looks a little like this:
Now you have something that hopefully resembles this, you need to move the copied layer under the visible Triple H layer. It is important to note that I used a chalk brush that I got with Photoshop to create the smudge and you too can do it by following the smudging tutorial that Doc set up above. After you have that, place the copied layer under the Triple H layer and set the copy to "Colour Burn" and you should have something that looks like this:
Now, that already looks pretty groovy but we are far from done. The next thing you want to do is save this as both a PNG file and a PSD file. That way, if you want to change anything, you can simply open the PSD and edit it. I wont be doing that though because I fucking rock and I also like to see what I can do without going back. So, save it as both and open the PNG file.
Now, the first thing I am going to do with this PNG file is mess with the levels, add a photo filter and a gradient map. I am sure I have covered all of those before and so I won't do it again. However, I will add that I am trying to make it dark as possible whilst still being sharp and not too dark that you cannot make anything out. If you are doing the same as me though, you will want to do these steps on new layers and after applying the image to those layers, reducing the opacity and setting the to overlay. So, here is what I have after doing those three, unessential, steps:
***More to come***
Last edited by Dave : 05-21-2010 at 06:27 PM.
You can already see that there is just a much more dynamic and sharpened picture that will flow well with the rest of the sig. Now, I am going to save what I have as a PNG and a PSD file and do the same as I did before, opening the PNG file after I have done this. Now, what I want to do is immediately duplicate the active layer and make the bottom layer, probably labelled "background" completely black and add a bit more canvas to it that will act as the border. It is essential to do this now as it will make things much easier down the line. So, with the black background layer active, hit "control + alt + c" to bring up the canvas dialogue box and make it 400 pixels by 200 pixels. You should have something that looks like this:
Now that you have that, it is time to go and select the other two renders that will flank the main render in the centre. I will pick two but do not feel that you have to pick the same two. I will be going with these two:
With those being chosen, it is time to go back to the original picture and select the top-most layer. Now, you want to click the button that adds a layer mask. That button should be on your layer panel and be right next to the "fx" button. Once you have done this, make sure that the layer mask is white and that you have a foreground colour of black. You should have this:
Now, by clicking on what is inside of the bottom circle, it will give you what is inside the bigger one at the top. You will then need to double-click on what is inside the top-most circle and then hit enter when the dialogue box pops up. You are now on the layer mask and will be painting on top of it. Now, with black selected as your foreground colour, go to your brushes panel and find the tear brushes and start painting on.
You can find those brushes here:
I got something that looks like this:
Now, I know that that looks like a bit of a mess at the moment but it will become clear in a minute. Now you have that, you need to click on the layer with the layer mask on it and hit the "fx" button and select stroke. Make it one pixel and in white. Then, go back into your fx panel and get drop shadow. Mess around with that until you have it looking like you want it to and hit OK. Once you have that, go around the bits you don't like with the eraser and you should end up with something that looks like this:
Now you have that, it is time to import the remainder of your pictures underneath the layer masked layer. What you should be looking to accomplish, is something that resembles this in your layers panel:
Now that you have that, you are almost done and done well. Now, just reposition things to your liking and you should have something that resembles this:
Now you have that, it is time to save the whole thing again and open the PNG file. You basically have what you want now but I am going to go to town with more gradient maps, burn and dodge tools and another photo filter. However, as a I said, these are not crucial but I tend to think that what is on the bottom should look pretty dark at this point. So, after messing around with a lot of the adjustments, I ended up with something like this:
Now that I have that, I am only going to add some text and a few more borders to show everything and we are all done. This is what I ended up with:
Congratulations and happy sigging.
Last edited by Dave : 06-03-2010 at 08:58 PM.
Hello again and welcome to another great sig tutorial brought to you by me and WrestleZone Forums. In this tutorial, we will be using some more advanced techniques and I will also be showing you some of the uses that C4D renders can have on a signature. Over the last couple of days, I have been using C4D renders a lot more so I can bring you this great tutorial to assist you in the future. As far as I know, C4D renders are pretty recent in the world of Digital graphics but I could be wrong. Nevertheless, I only recently tried to get used to them and see what I could come up with. With that in mind, let's get to work, amigos!
As always, links to the images and renders I use in this tutorial will be listed for you to follow along with. However, please feel free to post your results in your threads and leave any feedback in mine for this tutorial.
Today, we will be making a beastly Batman sig and here is what the resultant sig will likely look like:
Right, so first thing is first. Lets get the render that we are going to be working from:
Now we have that we can get on with making the signature. So, the first thing you want to do is open up your render on to a black canvas. I will be using a canvas that is 394 x 194 pixels for this task. Once you have done that, you should have something that looks like this:
Once you have that we need to work on our background. Now recently, I have been working with the sparkle brushes a lot and you could probably tell that from the sigs that line this thread. However, for a task like this, that is not really the effect we are looking for. With that in mind, paste in your render once more and keep it the original size. Move it around the canvas behind the render we already have and make sure that it covers the full canvas. You could even rotate them for more effect like I will be doing. Once you do that, you should have something like this:
To achieve what I have, I first put in the render and rotated it to the left and then rotated the second one to the right. Now, we have our background base done, what we want to do is make them the one layer. So, grab however many layers make up the area behind your render and merge them together. By this point, you should only have two layers and one of them should be your render layer and the other should be your background layer. With your background layer selected, we are going to go to:
Now, here is a quick note. I will be using PlanetRenders.net as my source of C4D's but you can get them from all over the place. I am using a rendered C4D for this but typing "C4D" into google will give you just the same results. Please also note that if you are following my tutorial and attempting the same result, you will need to be a member of PlanetRenders.net to download the same C4D.
After some searching, I have decided that I will be using this C4D:
So click on the thumbnail of the fractal C4D and it should bring up the actual image. You will need to save that to your computer before opening it up in Photoshop. Import the C4D onto your sig and place it where you want to have the flow. I like it behind Batman and I ended up with something that looks like this:
Once you have something like this, it is time to set it's blending mode. I like "Colour Burn" for this instance, so I am going to leave it on that. However, feel free to use whatever you think looks best and play around with the opacities. Also, if there is something that you don't like, feel free to erase it. After that, I am going to put in another C4D render and this time, I am going to use a render that seems to add some depth to your sig. After some searching, I decided to use this one:
What you want to do now, is use the same technique as before with the previous fractal render. Open it up in Photoshop, resize as appropriate and set that to "Linear Light". After you have done that, you will want to erase some of the C4D. I am erasing what is on the left of the C4D and leaving what is on the right. Once you have done that, you should have something that looks like this:
Now, immediately you can see the difference that the C4D's have made to the overall look of the signature. Everything looks like it flows much better and more depth is evident. After I have done that, I am going to duplicate my Batman render and set that on motion blur. Set the duplicated layer to something like "Colour Dodge" or whatever you prefer and merge the two render layers. Then merge the background layer with the two C4D layers and you should have this:
Now what you are going to do is take out your brush tool. Get a 65 pixel, soft edged bush and add a few dots of any colour that you feel fits in with the flow of your signature. I will be choosing a light blue as I feel the lighter colours work best. However, feel free to choose whichever ones you want. Add a few dots (on a new layer) to anywhere on the sig and set them to "soft light" and you should have something that looks like this:
I added some light marks to the left and right side of his cape, his chest and lastly the top, left-hand side of his mask to accentuate the light sources. Now, what we are going to do is apply the image. So go to:
Follow the same instructions as before and import that bad boy into the sig. Now, for this C4D, I had to do some editing. I first set it to "Linear Dodge" and then reduced the opacity to around 30 percent. After that, I erased everything that was either, to the left of my Batman render, or on top of it. Once you have done that, you should have something that looks like this:
More To Follow
Now, we are going to add a gradient map. So, make a new layer and go to:
Now, we are going to add another C4D layer that will make the flow of the sig better. I will be adding this one:
Again, you want to place it on there and erase anything that you think looks bad. You can set it to whatever you want but I am going to be setting it to Colour Dodge and then reducing the opacity down to around 50 percent once more. Once you have done that, you should have something that looks like this:
Now, create a new layer and fill it with black or a deep blue. Take out your brush tool and reduce the size of the stroke to something like 7 or 8 and add some dots on there. Then, put that layer on Linear Dodge and go to:
Again, I am going to add another C4D and see how it comes out. For the sake of following me, I will be using this one:
And following the same procedure as before. This time, I will be setting it to Soft Light and then reducing the opacity to 30 percent. Then, I am going to add some more light and dark shades to the signature. To do this, I will be using the same technique as I did before by taking two new layers and filling the with white and black and setting them to different blending modes. After you have done that, you should have something like this:
Next, what you need to do is create a new layer and apply the image once again. This time go to:
Now, all that remains is to add a border and a tag to the sig and we are all done! Here is what I had:
Congrats and happy Sigging!
OK, so as you might expect, the first thing you want to do is create a canvas with a filled out background. I made my canvas 400x300 because it fits the rules of this board and it also gets a nice poster size for the signature. Anyway, once I did that, I filled the canvas with a pale yellow colour. It should look like this:
Click for Spoiler:
Once you have that, you then need to take a new layer and start working on the brushing part of the signature. It took me a while to find some good brushes but I eventually got some that would work with this effect. Iuf you have your own, then fantastic. If not, here is the link for the download.
Once you have them, brush one of them on at full size and see how it goes. I chose red because that was the colour that was in the sample that was given to me by the person who requested this tutorial. So, I will be using red from this point on. Either way, it should look like this:
Click for Spoiler:
See, pretty simple, I am sure you will agree. Next, we need to find a render. For all the renders I have tried, this should work. However, you should try and find one with less intricate details for the best effect here. Something with flowing individual locks of hair will not work basically. Still, I chose a render of Bruce Springsteen for no apparent reason. This was the render I used:
You can see that this render already has a nice amount of contrast between the highlights and shadows and that is what you are looking for in the best case scenario. It also doesn't have so much colour that it will mess with the next step. The next step, possibly the hardest step for some, is managing to turn this render into a bi-coloured render that would fit into the style of the signature. I must admit that I had to fiddle with a couple of things until I found out how to do it. I knew it was possible though and managed it eventually. So, paste in your render and resize it how you like. I had something like this:
Click for Spoiler:
This part is the part that gets people all the time. What you need to do is duplicate the render and then go to Filter > Sketch > Stamp. It should be noted that your foreground and background colours will be taken into account here. So, have your foreground colour set as the colour you made your background and then set your background colour to a deep grey. Hit OK when it appears and you should have something like this:
Click for Spoiler:
It should be noted that I added a stroke of 15 to the render so that it stood out a little more against the background. Feel free to make it how you feel though. If you like it without the stroke, then keep it that way. Now, as you can see, the text might become a problem in the render. However, I have the easiest way of getting rid of it and it wont be a problem any more. Take out your marquee tool and select an area at the bottom of the signature. I covered all of the text and then filled it with a deep grey colour. When you have did this, you will need to have something along these lines:
Click for Spoiler:
Now, at this stage, you are almost done. I decided that I wanted more shadow down the right side and all I did was take out a soft brush on 9 pixels and brush in what I though would look best. I then put the text in and this is what it gave me:
Click for Spoiler:
Now add a big ass border to that canvas, I used 20 pixels, and you are done. Not as hard as it could have been, was it?
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Green Brook may be small, but this little town packs a punch when it comes to the dining scene. Here are some of the top places to eat, along with some customer reviews!
- Perkins Restaurant & Bakery: Enjoy all day breakfast in this cozy restaurant and feel at home with the friendly service and sumptuous servings.
"The host greets you with a good morning and asks how your day is - nice. The waitress (Giana) was very friendly and efficient. One of us had the basic eggs breakfast and the other a biscuits, chicken, gravy, eggs dish which was a little over the top in terms of calories and gravy and messiness. Got in and out on a busy Sunday." - B
"In my family this is the go to place for any breakfast event. We have also enjoyed lunch and dinner, but it can be breakfast once or twice a week." - JM
- Capital Craft: This gastropub offers excellent craft beers and impeccable small town hospitality. Drop by on their Happiest Hour enjoy half price off their beer, wine and cocktails!
"Had dinner there and enjoyed the beer samplers. The selected the beer we liked best. Had a good meal there too and started with fried Brussels sprouts. Very good food and craft beer nice atmosphere an good value for money. Highly recommend." - Bill
"Excellent place, excellent food and plenty on tap. Can't go wrong. Plenty of TV's. Great to watch the game and have a few with great food." - Joe
- Burnet Burger Plus: Fast food has never tasted this good! Gourmet burgers with USDA certified Angus Beef, homemade, freshly baked bread topped with fresh produce make this locally-owned place the best spot for your burger cravings!
"Heard Dennis mention this on NJ 101.5 radio as being really good. It certainly was! Service was fast and friendly, burgers were nice size portions and tasty. Overall, a very nice experience." - D
"One of the best burger joints I've been to so far. I've tried so many options from their menu and I'm never disappointed. They offer so many choices like the kind of bun (regular, onion, gluten free, lettuce wrap, regular wrap) and so many toppings. They don't stop at burgers though, there's a kids menu (which keeps my cousins happy whenever I bring them), turkey burgers, chicken sandwiches, hot dogs, steak sandwiches, milkshakes, fries, salads (yes, really good salads!), and vegetarian burgers. Honestly, I love going here because it's a good price and it's in a great location. Also the quality of the food is what makes this place so much better then the rest. Can't beat it. 100% recommend to everyone!!" - Raquel
- House of Thai Cuisine: Experience authentic Thai dishes in a restaurant that can only be described as absolutely the best Thai restaurant around!
"It was my second time here, this time we come the whole family for dinner. The food is good and and flavorful, we order few appetizers and the main dishes. The service was good and fast. I had the chicken with coconut and I asked to add some ginger and it was great. Everybody enjoy the meal and I took pictures of the dishes. I recommend this place, the food is fresh and resemble the Thai food I had in Chang Mai Thailand, so I know is it good." - I
"I haven't had Thai food this good since I've moved back east. Just as good as the home made Thai my California friends used to make! Red curry chicken and pad phed are absolutely killer. Service is beyond excellent! Highly recommend calling ahead for a table. Take out if fast and convenient as well!" - Sorah
- Carrabba's Italian Grill: The Green Brook branch of this chain provides the wonderful service you would come to expect from our small town. Experience a variety of authentic Italian goodness with their mouthwatering meals like flatbread pizza, lentil soup, and pasta!
"Do you hear me??? Best Italian restaurant ever. Food is excellent as well as the service. I would eat here 7 nights a week if I could, although I usually eat here about 5. It's my kitchen away from home" - Anna
"If you are looking for a good and reliable place to eat in the Green Brook, NJ area I would definitely recommend this place. The tomato caprese with fresh burrata was very good a spin of a Caprese salad. The sausage and Lentil soup was also very good and a little on the spicy side. The gilled sirloin was on the medium well side but it was still very good and still juicy. I would still recommend the meal. If you are in the area and are looking for a good meal, think about Carrabba's." - Augusto
- Blue Sheep Bake Shop: This bakeshop is a custom cake studio, gourmet cupcake bakery, and ice cream shop all rolled into one! Enjoy decadent milkshakes, sumptuous cupcakes, and coldly sweet ice cream sandwiches!
"We ordered our daughter's 1st birthday party cake wt Blue Sheep.....took a chance without ever eating a cake from the bakery. I relied strictly on recommendations and reviews. I am so glad that we decided to go with Blue Sheep. All I had to do was send Karin a picture of my daughter's 1st birthday shirt and she made it identical. My daughter and her cake matched perfectly! Not only did the cake look good, it tasted delicious. I would recommend Blue Sheep to everyone. You do get what you pay for!" - Kristin
- Green Cow Yogurt: Get your yogurt fix from Green Cow. Friendly owners and a smorgasbord of flavors make this a perfect place to chill and hang out!
"They sell Frozen Yogurt, Belgian Waffles and they have build your own Milkshakes. Many toppings to choose from. The fruit toppings are fresh. If you drive fast on Route 22 in Greenbrook you will miss it. It is at the Greenbrook Plaza within the strip mall." - Mary
"I stumbled upon Green Cow while driving through New Jersey from a GPS search for "frozen yogurt" and was so glad I did. I found a very clean, welcoming shop with a wide flavor and topping selection. The owner was incredibly friendly and hospitable. Can't say I will ever be in that part of NJ again any time soon, but if I am I will be sure to go back to Green Cow!" - Sue
Main Image Credit: Pexels