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Article ; Online: Carcinogenicity of ethylene oxide: key findings and scientific issues.

Jinot, Jennifer / Fritz, Jason M / Vulimiri, Suryanarayana V / Keshava, Nagalakshmi

2017 Volume 28, Issue 5, Page(s) 386–396

Abstract: In support of the Integrated Risk Information System (IRIS), the U.S. Environmental Protection Agency (EPA) completed an evaluation of the inhalation carcinogenicity of ethylene oxide (EtO) in December 2016. This article reviews key findings and ... ...

Abstract	In support of the Integrated Risk Information System (IRIS), the U.S. Environmental Protection Agency (EPA) completed an evaluation of the inhalation carcinogenicity of ethylene oxide (EtO) in December 2016. This article reviews key findings and scientific issues regarding the carcinogenicity of EtO in EPA's Carcinogenicity Assessment. EPA's assessment critically reviewed and characterized epidemiologic, laboratory animal, and mechanistic studies pertaining to the human carcinogenicity of EtO, and addressed some key scientific issues such as the analysis of mechanistic data as part of the cancer hazard evaluation and to inform the quantitative risk assessment. The weight of evidence from the epidemiologic, laboratory animal, and mechanistic studies supports a conclusion that EtO is carcinogenic in humans, with the strongest human evidence linking EtO exposure to lymphoid and breast cancers. Analyses of the mechanistic data establish a key role for genotoxicity and mutagenicity in EtO-induced carcinogenicity and reveal little evidence supporting other mode-of-action hypotheses. In conclusion, EtO was found to be carcinogenic to humans by inhalation, posing a potential human health hazard for lymphoid and breast cancers.
MeSH term(s)	Animals ; Breast Neoplasms/chemically induced ; Breast Neoplasms/epidemiology ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Carcinogenicity Tests ; Carcinogens/toxicity ; Cell Transformation, Neoplastic/chemically induced ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/pathology ; Ethylene Oxide/toxicity ; Female ; Humans ; Inhalation Exposure/adverse effects ; Lymphoproliferative Disorders/chemically induced ; Lymphoproliferative Disorders/epidemiology ; Lymphoproliferative Disorders/genetics ; Lymphoproliferative Disorders/pathology ; Male ; Models, Animal ; Mutagenicity Tests ; Risk Assessment
Chemical Substances	Carcinogens ; Ethylene Oxide (JJH7GNN18P)
Language	English
Publishing date	2017-12-21
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2081252-8
ISSN	1537-6524 ; 1537-6516 ; 1051-7235
ISSN (online)	1537-6524
ISSN	1537-6516 ; 1051-7235
DOI	10.1080/15376516.2017.1414343
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Article: Integrating publicly available information to screen potential candidates for chemical prioritization under the Toxic Substances Control Act: A proof of concept case study using genotoxicity and carcinogenicity.

Patlewicz, Grace / Dean, Jeffry L / Gibbons, Catherine F / Judson, Richard S / Keshava, Nagalakshmi / Vegosen, Leora / Martin, Todd M / Pradeep, Prachi / Simha, Anita / Warren, Sarah H / Gwinn, Maureen R / DeMarini, David M

Computational toxicology (Amsterdam, Netherlands)

2022 Volume 20, Page(s) 1–100185

Abstract: The Toxic Substances Control Act (TSCA) became law in the U.S. in 1976 and was amended in 2016. The amended law requires the U.S. EPA to perform risk-based evaluations of existing chemicals. Here, we developed a tiered approach to screen potential ... ...

Abstract	The Toxic Substances Control Act (TSCA) became law in the U.S. in 1976 and was amended in 2016. The amended law requires the U.S. EPA to perform risk-based evaluations of existing chemicals. Here, we developed a tiered approach to screen potential candidates based on their genotoxicity and carcinogenicity information to inform the selection of candidate chemicals for prioritization under TSCA. The approach was underpinned by a large database of carcinogenicity and genotoxicity information that had been compiled from various public sources. Carcinogenicity data included weight-of-evidence human carcinogenicity evaluations and animal cancer data. Genotoxicity data included bacterial gene mutation data from the
Language	English
Publishing date	2022-01-24
Publishing country	Netherlands
Document type	Journal Article
ISSN	2468-1113
ISSN	2468-1113
DOI	10.1016/j.comtox.2021.100185
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Article ; Online: Lymphohematopoietic cancers induced by chemicals and other agents and their implications for risk evaluation: An overview.

Eastmond, David A / Keshava, Nagalakshmi / Sonawane, Babasaheb

Mutation research. Reviews in mutation research

2014 Volume 761, Page(s) 40–64

Abstract: Lymphohematopoietic neoplasia are one of the most common types of cancer induced by therapeutic and environmental agents. Of the more than 100 human carcinogens identified by the International Agency for Research on Cancer, approximately 25% induce ... ...

Abstract	Lymphohematopoietic neoplasia are one of the most common types of cancer induced by therapeutic and environmental agents. Of the more than 100 human carcinogens identified by the International Agency for Research on Cancer, approximately 25% induce leukemias or lymphomas. The objective of this review is to provide an introduction into the origins and mechanisms underlying lymphohematopoietic cancers induced by xenobiotics in humans with an emphasis on acute myeloid leukemia, and discuss the implications of this information for risk assessment. Among the agents causing lymphohematopoietic cancers, a number of patterns were observed. Most physical and chemical leukemia-inducing agents such as the therapeutic alkylating agents, topoisomerase II inhibitors, and ionizing radiation induce mainly acute myeloid leukemia through DNA-damaging mechanisms that result in either gene or chromosomal mutations. In contrast, biological agents and a few immunosuppressive chemicals induce primarily lymphoid neoplasms through mechanisms that involve alterations in immune response. Among the environmental agents examined, benzene was clearly associated with acute myeloid leukemia in humans, with increasing but still limited evidence for an association with lymphoid neoplasms. Ethylene oxide and 1,3-butadiene were linked primarily to lymphoid cancers. Although the association between formaldehyde and leukemia remains controversial, several recent evaluations have indicated a potential link between formaldehyde and acute myeloid leukemia. The four environmental agents examined in detail were all genotoxic, inducing gene mutations, chromosomal alterations, and/or micronuclei in vivo. Although it is clear that rapid progress has been made in recent years in our understanding of leukemogenesis, many questions remain for future research regarding chemically induced leukemias and lymphomas, including the mechanisms by which the environmental agents reviewed here induce these diseases and the risks associated with exposures to such agents.
Language	English
Publishing date	2014-04-13
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2727833-5
ISSN	1388-2139 ; 1383-5742
ISSN (online)	1388-2139
ISSN	1383-5742
DOI	10.1016/j.mrrev.2014.04.001
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Article: Hazards of diethyl phthalate (DEP) exposure: A systematic review of animal toxicology studies

Weaver, James A / Beverly, Brandiese E.J / Keshava, Nagalakshmi / Mudipalli, Anuradha / Arzuaga, Xabier / Cai, Christine / Hotchkiss, Andrew K / Makris, Susan L / Yost, Erin E

Environment international. 2020 Dec., v. 145

2020

Abstract: Diethyl phthalate (DEP) is widely used in many commercially available products including plastics and personal care products. DEP has generally not been found to share the antiandrogenic mode of action that is common among other types of phthalates, but ... ...

Abstract	Diethyl phthalate (DEP) is widely used in many commercially available products including plastics and personal care products. DEP has generally not been found to share the antiandrogenic mode of action that is common among other types of phthalates, but there is emerging evidence that DEP may be associated with other types of health effects.To inform chemical risk assessment, we performed a systematic review to identify and characterize outcomes within six broad hazard categories (male reproductive, female reproductive, developmental, liver, kidney, and cancer) following exposure of nonhuman mammalian animals to DEP or its primary metabolite, monoethyl phthalate (MEP).A literature search was conducted in online scientific databases (PubMed, Web of Science, Toxline, Toxcenter) and Toxic Substances Control Act Submissions, augmented by review of online regulatory sources as well as forward and backward searches. Studies were selected for inclusion using PECO (Population, Exposure, Comparator, Outcome) criteria. Studies were evaluated using criteria defined a priori for reporting quality, risk of bias, and sensitivity using a domain-based approach. Evidence was synthesized by outcome and life stage of exposure, and strength of evidence was summarized into categories of robust, moderate, slight, indeterminate, or compelling evidence of no effect, using a structured framework.Thirty-four experimental studies in animals were included in this analysis. Although no effects on androgen-dependent male reproductive development were observed following gestational exposure to DEP, there was evidence including effects on sperm following peripubertal and adult exposures, and the overall evidence for male reproductive effects was considered moderate. There was moderate evidence that DEP exposure can lead to developmental effects, with the major effect being reduced postnatal growth following gestational or early postnatal exposure; this generally occurred at doses associated with maternal effects, consistent with the observation that DEP is not a potent developmental toxicant. The evidence for liver effects was considered moderate based on consistent changes in relative liver weight at higher dose levels; histopathological and biochemical changes indicative of hepatic effects were also observed, but primarily in studies that had significant concerns for risk of bias and sensitivity. The evidence for female reproductive effects was considered slight based on few reports of statistically significant effects on maternal body weight gain, organ weight changes, and pregnancy outcomes. Evidence for cancer and effects on kidney were judged to be indeterminate based on limited evidence (i.e., a single two-year cancer bioassay) and inconsistent findings, respectively.These results suggest that DEP exposure may induce androgen-independent male reproductive toxicity (i.e., sperm effects) as well as developmental toxicity and hepatic effects, with some evidence of female reproductive toxicity. More research is warranted to fully evaluate these outcomes and strengthen confidence in this database.
Keywords	adults ; bioassays ; body weight changes ; chemical risk assessment ; databases ; developmental toxicity ; diethyl phthalate ; environment ; females ; histopathology ; kidneys ; liver ; males ; mammals ; maternal exposure ; mechanism of action ; metabolites ; reproductive toxicology ; risk ; spermatozoa ; systematic review ; tissue weight
Language	English
Dates of publication	2020-12
Publishing place	Elsevier Ltd
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	554791-x
ISSN	1873-6750 ; 0160-4120
ISSN (online)	1873-6750
ISSN	0160-4120
DOI	10.1016/j.envint.2020.105848
Database	NAL-Catalogue (AGRICOLA)

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Article: Evaluation of Existing QSAR Models and Structural Alerts and Development of New Ensemble Models for Genotoxicity Using a Newly Compiled Experimental Dataset.

Pradeep, Prachi / Judson, Richard / DeMarini, David M / Keshava, Nagalakshmi / Martin, Todd M / Dean, Jeffry / Gibbons, Catherine F / Simha, Anita / Warren, Sarah H / Gwinn, Maureen R / Patlewicz, Grace

Computational toxicology (Amsterdam, Netherlands)

2021 Volume 18

Abstract: Regulatory agencies world-wide face the challenge of performing risk-based prioritization of thousands of substances in commerce. In this study, a major effort was undertaken to compile a large genotoxicity dataset (54,805 records for 9299 substances) ... ...

Abstract	Regulatory agencies world-wide face the challenge of performing risk-based prioritization of thousands of substances in commerce. In this study, a major effort was undertaken to compile a large genotoxicity dataset (54,805 records for 9299 substances) from several public sources (e.g., TOXNET, COSMOS, eChemPortal). The names and outcomes of the different assays were harmonized, and assays were annotated by type: gene mutation in
Language	English
Publishing date	2021-09-09
Publishing country	Netherlands
Document type	Journal Article
ISSN	2468-1113
ISSN	2468-1113
DOI	10.1016/j.comtox.2021.100167
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Article: Use and application of mode of action in cancer risk assessment.

Keshava, Nagalakshmi / Eastmond, David

Environmental and molecular mutagenesis

2008 Volume 49, Issue 2, Page(s) 97–99

MeSH term(s)	Animals ; Humans ; Neoplasms/etiology ; Risk Assessment/methods
Language	English
Publishing date	2008-03
Publishing country	United States
Document type	Editorial ; Introductory Journal Article
ZDB-ID	639145-x
ISSN	1098-2280 ; 0893-6692
ISSN (online)	1098-2280
ISSN	0893-6692
DOI	10.1002/em.20371
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Article: Use and Application of Mode of Action in Cancer Risk Assessment

Keshava, Nagalakshmi / Eastmond, David

Environmental and molecular mutagenesis. 2008 Mar., v. 49, no. 2

2008

Language	English
Dates of publication	2008-03
Size	p. 97-99.
Publishing place	Wiley Subscription Services, Inc., A Wiley Company
Document type	Article
ZDB-ID	639145-x
ISSN	0893-6692
ISSN	0893-6692
DOI	10.1002/em.20371
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Article ; Online: Hazards of diethyl phthalate (DEP) exposure: A systematic review of animal toxicology studies.

Weaver, James A / Beverly, Brandiese E J / Keshava, Nagalakshmi / Mudipalli, Anuradha / Arzuaga, Xabier / Cai, Christine / Hotchkiss, Andrew K / Makris, Susan L / Yost, Erin E

Environment international

2020 Volume 145, Page(s) 105848

Abstract: Background: Diethyl phthalate (DEP) is widely used in many commercially available products including plastics and personal care products. DEP has generally not been found to share the antiandrogenic mode of action that is common among other types of ... ...

Abstract	Background: Diethyl phthalate (DEP) is widely used in many commercially available products including plastics and personal care products. DEP has generally not been found to share the antiandrogenic mode of action that is common among other types of phthalates, but there is emerging evidence that DEP may be associated with other types of health effects. Objective: To inform chemical risk assessment, we performed a systematic review to identify and characterize outcomes within six broad hazard categories (male reproductive, female reproductive, developmental, liver, kidney, and cancer) following exposure of nonhuman mammalian animals to DEP or its primary metabolite, monoethyl phthalate (MEP). Methods: A literature search was conducted in online scientific databases (PubMed, Web of Science, Toxline, Toxcenter) and Toxic Substances Control Act Submissions, augmented by review of online regulatory sources as well as forward and backward searches. Studies were selected for inclusion using PECO (Population, Exposure, Comparator, Outcome) criteria. Studies were evaluated using criteria defined a priori for reporting quality, risk of bias, and sensitivity using a domain-based approach. Evidence was synthesized by outcome and life stage of exposure, and strength of evidence was summarized into categories of robust, moderate, slight, indeterminate, or compelling evidence of no effect, using a structured framework. Results: Thirty-four experimental studies in animals were included in this analysis. Although no effects on androgen-dependent male reproductive development were observed following gestational exposure to DEP, there was evidence including effects on sperm following peripubertal and adult exposures, and the overall evidence for male reproductive effects was considered moderate. There was moderate evidence that DEP exposure can lead to developmental effects, with the major effect being reduced postnatal growth following gestational or early postnatal exposure; this generally occurred at doses associated with maternal effects, consistent with the observation that DEP is not a potent developmental toxicant. The evidence for liver effects was considered moderate based on consistent changes in relative liver weight at higher dose levels; histopathological and biochemical changes indicative of hepatic effects were also observed, but primarily in studies that had significant concerns for risk of bias and sensitivity. The evidence for female reproductive effects was considered slight based on few reports of statistically significant effects on maternal body weight gain, organ weight changes, and pregnancy outcomes. Evidence for cancer and effects on kidney were judged to be indeterminate based on limited evidence (i.e., a single two-year cancer bioassay) and inconsistent findings, respectively. Conclusions: These results suggest that DEP exposure may induce androgen-independent male reproductive toxicity (i.e., sperm effects) as well as developmental toxicity and hepatic effects, with some evidence of female reproductive toxicity. More research is warranted to fully evaluate these outcomes and strengthen confidence in this database.
MeSH term(s)	Animals ; Female ; Liver ; Male ; Neoplasms ; Phthalic Acids/toxicity ; Pregnancy ; Reproduction ; Risk Assessment
Chemical Substances	Phthalic Acids ; diethyl phthalate (UF064M00AF)
Language	English
Publishing date	2020-09-19
Publishing country	Netherlands
Document type	Journal Article ; Review ; Systematic Review
ZDB-ID	554791-x
ISSN	1873-6750 ; 0160-4120
ISSN (online)	1873-6750
ISSN	0160-4120
DOI	10.1016/j.envint.2020.105848
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Article: Application of systematic evidence mapping to assess the impact of new research when updating health reference values: A case example using acrolein

Keshava, Channa / Davis, J. Allen / Stanek, John / Thayer, Kristina A / Galizia, Audrey / Keshava, Nagalakshmi / Gift, Jeff / Vulimiri, Suryanarayana V / Woodall, George / Gigot, Carolyn / Garcia, Kelly / Greenhalgh, Andrew / Schulz, Brittany / Volkoff, Savannah / Camargo, Krisa / Persad, Amanda S

Environment international. 2020 Oct., v. 143

2020

Abstract: The environmental health community needs transparent, methodologically rigorous, and rapid approaches for updating human health risk assessments. These assessments often contain reference values for cancer and/or noncancer effects. Increasingly, the use ... ...

Abstract	The environmental health community needs transparent, methodologically rigorous, and rapid approaches for updating human health risk assessments. These assessments often contain reference values for cancer and/or noncancer effects. Increasingly, the use of systematic review methods are preferred when developing these assessments. Systematic evidence maps are a type of analysis that has the potential to be very helpful in the update process, especially when combined with machine-learning software advances designed to expedite the process of conducting a review.To evaluate the applicability of evidence mapping to determine whether new evidence is likely to result in a change to an existing health reference value, using inhalation exposure to the air pollutant acrolein as a case example.New literature published since the 2008 California Environmental Protection Agency’s Office of Environmental Health Hazard Assessment (OEHHA) Reference Exposure Level (REL) for acrolein was assessed. Systematic review methods were used to search the literature and screening included the use of machine-learning software. The Populations, Exposures, Comparators and Outcomes (PECO) criteria were kept broad to identify studies that characterized acute and chronic exposure and could be informative for hazard characterization. Studies that met the PECO criteria after full-text review were briefly summarized before their suitability for chronic point of departure (POD) derivation and calculation of a reference value was considered. Studies considered potentially suitable underwent a targeted evaluation to determine their suitability for use in dose–response analysis.Over 15,000 studies were identified from scientific databases. Both machine-learning and manual screening processes were used to identify 60 studies considered PECO-relevant after full-text review. Most of these PECO-relevant studies were short-term exposure animal studies (acute or less than 1 month of exposure) and considered less suitable for deriving a chronic reference value when compared to the subchronic study in rats used in the 2008 OEHHA assessment. Thirteen epidemiological studies were identified but had limitations in the exposure assessment that made them less suitable for dose–response compared to the subchronic rat study. Among the 13 studies, there were four controlled trial studies that have the potential to be informative for future acute reference value derivation. Thus, the 2008 subchronic rat study used by OEHHA appears to still be the most appropriate study for chronic reference value derivation. In addition, advances in dosimetric modeling for gases, including new evidence pertinent to acrolein, could be considered when updating existing acrolein toxicity values.Evidence mapping is a very useful tool to assess the need for updating an assessment based on understanding the potential impact of new studies on revising an existing health reference value. In this case example, the focus was to identify studies suitable for chronic exposure dose–response analysis, while also identifying studies that may be important to consider for acute exposure scenarios, hazard identification, or for future research. This allows the evidence map to be a useful resource for a range of decision-making contexts. Specialized systematic review software increased the efficiency of the process in terms of human resources and time to conduct the analysis.
Keywords	acrolein ; acute exposure ; air pollutants ; artificial intelligence ; chronic exposure ; computer software ; decision making ; dose response ; environment ; environmental hazards ; environmental health ; environmental protection ; exposure assessment ; hazard characterization ; hazard identification ; human health ; humans ; inhalation exposure ; rats ; risk ; systematic review ; toxicity ; California
Language	English
Dates of publication	2020-10
Publishing place	Elsevier Ltd
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	554791-x
ISSN	1873-6750 ; 0160-4120
ISSN (online)	1873-6750
ISSN	0160-4120
DOI	10.1016/j.envint.2020.105956
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Article: Key issues in the role of peroxisome proliferator-activated receptor agonism and cell signaling in trichloroethylene toxicity.

Keshava, Nagalakshmi / Caldwell, Jane C

Environmental health perspectives

2006 Volume 114, Issue 9, Page(s) 1464–1470

Abstract: Peroxisome proliferator-activated receptor alpha (PPARalpha) is thought to be involved in several different diseases, toxic responses, and receptor pathways. The U.S. Environmental Protection Agency 2001 draft trichloroethylene (TCE) risk assessment ... ...

Abstract	Peroxisome proliferator-activated receptor alpha (PPARalpha) is thought to be involved in several different diseases, toxic responses, and receptor pathways. The U.S. Environmental Protection Agency 2001 draft trichloroethylene (TCE) risk assessment concluded that although PPAR may play a role in liver tumor induction, the role of its activation and the sequence of subsequent events important to tumorigenesis are not well defined, particularly because of uncertainties concerning the extraperoxisomal effects. In this article, which is part of a mini-monograph on key issues in the health risk assessment of TCE, we summarize some of the scientific literature published since that time on the effects and actions of PPARalpha that help inform and illustrate the key scientific questions relevant to TCE risk assessment. Recent analyses of the role of PPARalpha in gene expression changes caused by TCE and its metabolites provide only limited data for comparison with other PPARalpha agonists, particularly given the difficulties in interpreting results involving PPARalpha knockout mice. Moreover, the increase in data over the last 5 years from the broader literature on PPARalpha agonists presents a more complex array of extraperoxisomal effects and actions, suggesting the possibility that PPARalpha may be involved in modes of action (MOAs) not only for liver tumors but also for other effects of TCE and its metabolites. In summary, recent studies support the conclusion that determinations of the human relevance and susceptibility to PPARalpha-related MOA(s) of TCE-induced effects cannot rely on inferences regarding peroxisome proliferation per se and require a better understanding of the interplay of extraperoxisomal events after PPARalpha agonism.
MeSH term(s)	Animals ; Carcinogenicity Tests ; Environmental Pollutants/metabolism ; Environmental Pollutants/toxicity ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/physiology ; History, 21st Century ; Humans ; Liver Neoplasms/chemically induced ; PPAR alpha/agonists ; PPAR alpha/physiology ; Risk Assessment ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Trichloroethylene/metabolism ; Trichloroethylene/toxicity ; United States ; United States Environmental Protection Agency
Chemical Substances	Environmental Pollutants ; PPAR alpha ; Trichloroethylene (290YE8AR51)
Language	English
Publishing date	2006-09
Publishing country	United States
Document type	Historical Article ; Journal Article ; Review
ZDB-ID	195189-0
ISSN	1552-9924 ; 0091-6765 ; 1078-0475
ISSN (online)	1552-9924
ISSN	0091-6765 ; 1078-0475
DOI	10.1289/ehp.8693
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