[Show abstract][Hide abstract] ABSTRACT: Benzene, a ubiquitous environmental pollutant, causes acute myeloid leukemia (AML). Recently, through transcriptome profiling of peripheral blood mononuclear cells (PBMC), we reported dose-dependent effects of benzene exposure on gene expression and biochemical pathways in 83 workers exposed across four airborne concentration ranges (from <1 ppm to >10 ppm) compared with 42 subjects with non-workplace ambient exposure levels. Here, we further characterize these dose-dependent effects with continuous benzene exposure in all 125 study subjects. We estimated air benzene exposure levels in the 42 environmentally-exposed subjects from their unmetabolized urinary benzene levels. We used a novel non-parametric, data-adaptive model selection method to estimate the change with dose in the expression of each gene. We describe non-parametric approaches to model pathway responses and used these to estimate the dose responses of the AML pathway and 4 other pathways of interest. The response patterns of majority of genes as captured by mean estimates of the first and second principal components of the dose-response for the five pathways and the profiles of 6 AML pathway response-representative genes (identified by clustering) exhibited similar apparent supra-linear responses. Responses at or below 0.1 ppm benzene were observed for altered expression of AML pathway genes and CYP2E1. Together, these data show that benzene alters disease-relevant pathways and genes in a dose-dependent manner, with effects apparent at doses as low as 100 ppb in air. Studies with extensive exposure assessment of subjects exposed in the low-dose range between 10 ppb and 1 ppm are needed to confirm these findings.
[Show abstract][Hide abstract] ABSTRACT: The Ramazzini Institute (RI) has completed nearly 400 cancer bioassays on over 200 compounds. Study design and protocol differences between RI and other laboratories have been suggested by the European Food Safety Authority (EFSA) and others to contribute to controversy regarding cancer hazard findings, principally lymphoma/leukemia diagnoses.
Evaluate RI study design, protocol differences, and accuracy of tumor diagnoses for their impact on carcinogenic hazard characterization.
We analyzed the findings from a recent Pathology Working Group (PWG) review of RI procedures and tumor diagnoses, evaluated consistency of RI and other laboratory findings for chemicals identified by RI as positive for lymphoma/leukemia, and examined evidence for a number of other issues raised regarding RI bioassays. The RI cancer bioassay design and protocols were evaluated in the context of relevant risk assessment guidance from International authorities.
Although the PWG identified close agreement with RI diagnoses for most tumor types, it did not for lymphoma/leukemia of the respiratory tract and neoplasms of the inner ear and cranium. We discuss (1) the implications of the PWG findings, particularly lymphoma diagnostic issues, (2) differences between RI and other laboratory studies that are relevant to evaluating RI cancer bioassays and (3) future work that may help resolve some concerns.
We conclude that (1) issues related to respiratory tract infections have complicated diagnoses at that site (i.e., lymphoma/leukemia) and for neoplasms of the inner ear and cranium, and (2) there is consistency and value in RI studies for identification of other chemical-related neoplasia.
Full-text · Article · Sep 2013 · Environmental Health Perspectives
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Dec 2012 · Environmental Health Perspectives
[Show abstract][Hide abstract] ABSTRACT: We conducted a meta-analysis focusing on studies with high potential for trichloroethylene (TCE) exposure to provide quantitative evaluations of the evidence for associations between TCE exposure and kidney, liver, and non-Hodgkin lymphoma (NHL) cancers. A systematic review documenting essential design features, exposure assessment approaches, statistical analyses, and potential sources of confounding and bias identified twenty-four cohort and case-control studies on TCE and the three cancers of interest with high potential for exposure, including five recently published case-control studies of kidney cancer or NHL. Fixed- and random-effects models were fitted to the data on overall exposure and on the highest exposure group. Sensitivity analyses examined the influence of individual studies and of alternative risk estimate selections. For overall TCE exposure and kidney cancer, the summary relative risk (RRm) estimate from the random effects model was 1.27 (95% CI: 1.13, 1.43), with a higher RRm for the highest exposure groups (1.58, 95% CI: 1.28, 1.96). The RRm estimates were not overly sensitive to alternative risk estimate selections or to removal of an individual study. There was no apparent heterogeneity or publication bias. For NHL, RRm estimates for overall exposure and for the highest exposure group, respectively, were 1.23 (95% CI: 1.07, 1.42) and 1.43 (95% CI: 1.13, 1.82) and, for liver cancer, 1.29 (95% CI: 1.07, 1.56) and 1.28 (95% CI: 0.93, 1.77). Our findings provide strong support for a causal association between TCE exposure and kidney cancer. The support is strong but less robust for NHL, where issues of study heterogeneity, potential publication bias, and weaker exposure-response results contribute uncertainty, and more limited for liver cancer, where only cohort studies with small numbers of cases were available.
Preview · Article · Nov 2011 · International Journal of Environmental Research and Public Health
[Show abstract][Hide abstract] ABSTRACT: Objectives Two advisory panels reviewing the epidemiologic evidence on cancer and trichlorethylene (TCE) recommended meta-analysis as an approach to synthesise epidemiologic data, noting individual studies had limited statistical power for relatively uncommon cancers such as kidney, liver, and non-Hodgkin lymphoma (NHL) (NRC, 2006; Ward et al, 2010). We have conducted analyses focusing on studies with rigorous exposure definitions to provide quantitative evaluations of the evidence for associations between TCE and these specific cancers.
Methods A systematic review of over 70 studies on TCE and cancer documented essential design features, exposure assessment approaches, statistical analyses, and potential sources of confounding and bias. Twenty-four cohort and case-control studies with high exposure potential were identified. Fixed and random effects models were fitted to the data on overall exposure and on the highest exposure group. Sensitivity analyses examined the influence of alternative risk estimate selections.
Results For overall TCE exposure and kidney cancer, the summary risk estimate (RRm) from the fixed effect model was 1.27 (95% CI 1.13 to 1.43) with a higher RRm for the highest exposure groups (1.58, 95% CI 1.28 to 1.96). The RRm were not overly sensitive to alternative selections or to removal of an individual study. There was no apparent heterogeneity or publication bias. Less evidence was found for liver cancer and NHL.
Conclusions Our findings support an association between TCE exposure and kidney cancer. Disclaimer: The findings and conclusions in this abstract are those of the authors and do not necessarily represent the views of the U.S. Environmental Protection Agency.
Preview · Article · Oct 2011 · Occupational and Environmental Medicine
[Show abstract][Hide abstract] ABSTRACT: In occupational studies, which are commonly used for risk assessment for environmental settings, estimated exposure-response relationships often attenuate at high exposures. Relative risk (RR) models with transformed (e.g., log- or square root-transformed) exposures can provide a good fit to such data, but resulting exposure-response curves that are supralinear in the low-dose region may overestimate low-dose risks. Conversely, a model of untransformed (linear) exposure may underestimate risks attributable to exposures in the low-dose region.
We examined several models, seeking simple parametric models that fit attenuating exposure-response data well. We have illustrated the use of both log-linear and linear RR models using cohort study data on breast cancer and exposure to ethylene oxide.
Linear RR models fit the data better than do corresponding log-linear models. Among linear RR models, linear (untransformed), log-transformed, square root-transformed, linear-exponential, and two-piece linear exposure models all fit the data reasonably well. However, the slopes of the predicted exposure-response relations were very different in the low-exposure range, which resulted in different estimates of the exposure concentration associated with a 1% lifetime excess risk (0.0400, 0.00005, 0.0016, 0.0113, and 0.0100 ppm, respectively). The linear (in exposure) model underestimated the categorical exposure-response in the low-dose region, whereas log-transformed and square root-transformed exposure models overestimated it.
Although a number of models may fit attenuating data well, models that assume linear or nearly linear exposure-response relations in the low-dose region of interest may be preferred by risk assessors, because they do not depend on the choice of a point of departure for linear low-dose extrapolation and are relatively easy to interpret.
Full-text · Article · Jan 2011 · Environmental Health Perspectives
[Show abstract][Hide abstract] ABSTRACT: Diverse environmental contaminants, including the plasticizer di(2-ethylhexyl)phthalate (DEHP), are hepatocarcinogenic peroxisome proliferators in rodents. Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activation and its sequelae have been proposed to constitute a mode of action (MOA) for hepatocarcinogenesis by such agents as a sole causative factor. Further, based on a hypothesized lower sensitivity of humans to this MOA, prior reviews have concluded that rodent hepatocarcinogenesis by PPAR-alpha agonists is irrelevant to human carcinogenic risk.
Herein, we review recent studies that experimentally challenge the PPAR-alpha activation MOA hypothesis, providing evidence that DEHP is hepatocarcinogenic in PPAR-alpha-null mice and that the MOA but not hepatocarcinogenesis is evoked by PPAR-alpha activation in a transgenic mouse model. We further examine whether relative potency for PPAR-alpha activation or other steps in the MOA correlates with tumorigenic potency. In addition, for most PPAR-alpha agonists of environmental concern, available data are insufficient to characterize relative human sensitivity to this rodent MOA or to induction of hepatocarcinogenesis.
Our review and analyses raise questions about the hypothesized PPAR-alpha activation MOA as a sole explanation for rodent hepatocarcinogenesis by PPAR-alpha agonists and therefore its utility as a primary basis for assessing human carcinogenic risk from the diverse compounds that activate PPAR-alpha. These findings have broad implications for how MOA hypotheses are developed, tested, and applied in human health risk assessment. We discuss alternatives to the current approaches to these key aspects of mechanistic data evaluation.
Full-text · Article · Nov 2009 · Environmental Health Perspectives
[Show abstract][Hide abstract] ABSTRACT: Our objective was to examine experimental and epidemiologic studies pertaining to immune-related, and specifically autoimmune-related, effects of trichloroethylene (TCE).
We performed a literature search of PubMed and reviewed bibliographies in identified articles. We then systematically reviewed immune-related data, focusing on clinical and immunologic features and mechanistic studies.
Studies conducted in MRL+/+ lupus mice report an accelerated autoimmune response in relation to exposure to TCE or some metabolites. Effects have been reported after 4 weeks of exposure to TCE at doses as low as 0.1 mg/kg/day in drinking water and have included increased antinuclear antibodies and interferon-gamma (IFN-gamma) and decreased secretion of interleukin-4 (IL-4), consistent with an inflammatory response. Autoimmune hepatitis, inflammatory skin lesions, and alopecia have been found after exposures of 32-48 weeks. Recent mechanistic experiments in mice examined oxidative stress and, specifically, effects on lipid-peroxidation-derived aldehydes in TCE-induced autoimmune disease. Two studies in humans reported an increase in IL-2 or IFN-gamma and a decrease in IL-4 in relation to occupational or environmental TCE exposure. Occupational exposure to TCE has also been associated with a severe, generalized hypersensitivity skin disorder accompanied by systemic effects, including hepatitis. In three case-control studies of scleroderma with a measure of occupational TCE exposure, the combined odds ratio was 2.5 [95% confidence interval (CI), 1.1-5.4] in men and 1.2 (95% CI, 0.58-2.6) in women.
The consistency among the studies and the concordance between the studies in mice and humans support an etiologic role of TCE in autoimmune disease. Multisite collaborations and studies of preclinical immune markers are needed to further develop this field of research.
Preview · Article · Jun 2009 · Environmental Health Perspectives
[Show abstract][Hide abstract] ABSTRACT: The European Food Safety Authority (EFSA) released a 2006 report questioning the relationship of aspartame exposure with increased incidence of lymphomas/leukemias in a European Ramazzini Foundation (ERF) rat study. The EFSA report suggested that the lymphoma/leukemia findings were most likely explained by infection in the rat colony. The ERF has also conducted the only available long-term oral study of methyl tertiary-butyl ether (MTBE). Thus, using the EFSA report as support, some have now raised questions about the human relevance of MTBE-associated hemolymphoreticular tumors reported by the ERF in female rats as well as whether their incidence was elevated above background levels. In this report, we discuss the hypothesized mode of action (MOA) of infection-induced lymphoma and its relevance to MTBE-associated lymphomas. We address the relationship of rat strain and study duration to lymphoma susceptibility and review evidence of low background rates of this tumor in control animals at the ERF, similar survival rates for female rats at the ERF and National Toxicology Program (NTP), and chemical- and gender-specificity of tumor induction for this type of tumor in studies at the ERF. We find that the background incidence of hemolymphoreticular tumors in female rats in the MTBE study is consistent with contemporaneous studies at the ERF and that there is an exposure-related effect, which is unlikely to be due to infections. We examine more recent tumor classification schemes for lymphomas, which support the combination of lymphoblastic leukemias and lymphomas reported by Belpoggi et al. ( Toxicol Ind Health 11:119-149;  Eur J Oncol 3:201-206).
No preview · Article · Mar 2008 · Environmental and Molecular Mutagenesis
[Show abstract][Hide abstract] ABSTRACT: Mode of action (MOA) information is increasingly being applied in human health risk assessment. The MOA can inform issues such as the relevance of observed effects in laboratory animals to humans, and the variability of response within the human population. Several collaborative groups have developed frameworks for analyzing and utilizing MOA information in human health risk assessment of environmental carcinogens and toxins, including the International Programme on Chemical Safety, International Life Sciences Institute, and U.S. Environmental Protection Agency. With the goal of identifying gaps and opportunities for progress, we critically evaluate several of these MOA frameworks. Despite continued improvement in incorporating biological data in human health risk assessment, several notable challenges remain. These include articulation of the significant role of scientific judgment in establishing an MOA and its relevance to humans. In addition, binary (yes/no) decisions can inappropriately exclude consideration of data that may nonetheless be informative to the overall assessment of risk. Indeed, the frameworks lack a broad consideration of known causes of human disease and the potential for chemical effects to act additively with these as well as endogenous background processes. No integrated analysis of the impact of multiple MOAs over the same dose range, or of varying MOAs at different life stages, is included. Separate consideration of each MOA and outcome limits understanding of how multiple metabolites, modes, and toxicity pathways contribute to the toxicological profile of the chemical. An extension of the analyses across outcomes with common modes is also needed.
No preview · Article · Feb 2008 · Journal of Toxicology and Environmental Health Part B