Pathway-Based Toxicity: History, Current Approaches and Liver Fibrosis and Steatosis as Prototypes

The Human Toxicology Project Consortium (HTPC) was created to accelerate implementation of the science and policies required to achieve a pathway-based foundation for toxicology as articulated in the 2007 National Research Council report, Toxicity Testing in the 21st Century: a Vision and a Strategy. The HTPC held a workshop, “Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology: Liver Toxicity Mode-of-Action,” in January, 2013, in Baltimore, MD, to further the science of pathway-based approaches to liver toxicity. This review was initiated as a thought-starter for this workshop and has since been updated to include insights from the workshop and other activities occurring in 2013. The report of the workshop has been published elsewhere in this journal (Willett, 2014).JRC.I.5-Systems Toxicolog

Exile Vol. XLII No. 1

40th Year Title Page by Sakura Yamamoto \u2797 i Epigraph by Ezra Pound ii Table of Contents iii / Untitled (artwork) by Gretchen Hambly \u2796 iv Breughel Again, Brussels by Adrienne Fair \u2796 1 for play with whitman by alex e blazer \u2797 4 Saeta Sunday by Carl Boon \u2796 5 An Abbreviated Life by Mike Westmoreland 6 Anthem of Governor\u27s Bay by Jamey Hein \u2796 7-10 Time is everywhere, yet nowhere (artwork) by Susanne Ducker \u2796 11 Crosses by Liz Bolyard \u2796 12 Raccoons at the Cats\u27 Food by Jennifer Rudgers \u2796 13-14 Father Federico by Trish Klei \u2797 15 Dream Poem I by Colin Bossen \u2798 16 Virgin Mary in Kentucky by Amy Ard \u2796 17 the jig is up by alex e blazer \u2797 18-20 Visiting Uncle Ernie by Liz Bolyard \u2796 21-22 A Capuchin Monk by Linda Fuller-Smith 23 Sunday, October 15, 1995 by Carl Boon \u2796 24 Old Man and the Marriage Party by Trish Klei \u2797 25 Untitled (artwork) by Gretchen Hambly \u2796 26 Cowboy Up by J. Murdoch Be Matheson \u2796 27-34 Fragments by Colin Bossen \u2798 35 meditation (artwork) by alex e blazer \u2797 36 Palazzo Rezzonico by Linda Fuller-Smith 37 A Poem About The Photographic Imprint I Would Leave If A Nuclear Bomb Hit Nearby As I Took Out The Trash One Night by Trish Klei \u2797 38 The Crazies I\u27ve Called by Julie Johnston \u2796 39-46 Contributors\u27 Notes 47-48 Editorial Board 49 Editorial decisions are shared equally among the Editorial Board. -49 Cover art by alex emmons -4

ESAC Opinion on the Scientific Validity of the AR-CALUX Test Method

ESAC, the EURL ECVAM Scientific Advisory Committee, advises EURL ECVAM on scientific issues. Its main role is to conduct independent peer review of validation studies of alternative test methods and to assess their scientific validity for a given purpose. The committee reviews the appropriateness of study design and management, the quality of results obtained and the plausibility of the conclusions drawn. ESAC peer reviews are formally initiated with a EURL ECVAM Request for ESAC Advice, which provides the necessary background for the peer-review and establishes its objectives, timelines and the questions to be addressed. The peer review is normally prepared by specialised ESAC Working Groups. ESAC's advice to EURL ECVAM is formally provided as 'ESAC Opinions' and 'Working Group Reports' at the end of the peer review. ESAC may also issue Opinions on other scientific issues of relevance to the work and mission of EURL ECVAM but not directly related to a specific alternative test method. The ESAC Opinion expressed in this report relates to the peer-review of the AR-CALUX in vitro test method.JRC.F.3-Chemicals Safety and Alternative Method

ESAC Opinion on the Scientific Validity of the Bioelution Test Method: ESAC Opinion No. 2019-03 of 2 December 2019

ESAC, the EURL ECVAM Scientific Advisory Committee, advises EURL ECVAM on scientific issues. Its main role is to conduct independent peer review of validation studies of alternative test methods and to assess their scientific validity for a given purpose. The committee reviews the appropriateness of study design and management, the quality of results obtained and the plausibility of the conclusions drawn. ESAC peer reviews are formally initiated with a EURL ECVAM Request for ESAC Advice, which provides the necessary background for the peer-review and establishes its objectives, timelines and the questions to be addressed. The peer review is normally prepared by specialised ESAC Working Groups. ESAC's advice to EURL ECVAM is formally provided as 'ESAC Opinions' and 'Working Group Reports' at the end of the peer review. ESAC may also issue Opinions on other scientific issues of relevance to the work and mission of EURL ECVAM but not directly related to a specific alternative test method. The ESAC Opinion expressed in this report relates to the peer-review of the Bioelution in vitro test method.JRC.F.3-Chemicals Safety and Alternative Method

Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology: Liver Toxicity Mode-of-Action

A workshop sponsored by the Human Toxicology Project Consortium (HTPC), “Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology: Liver Toxicity Mode-of-Action” brought together experts from a wide range of perspectives to inform the process of pathway development and to advance two prototype pathways initially developed by the European Commission Joint Research Center (JRC): liver-specific fibrosis and steatosis. The first half of the workshop focused on the theory and practice of pathway development; the second on liver disease and the two prototype pathways. Participants agreed pathway development is extremely useful for organizing information and found that focusing the theoretical discussion on a specific AOP is helpful. It is important to include several perspectives during pathway development, including information specialists, pathologists, human health and environmental risk assessors, and chemical and product manufacturers, to ensure the biology is well captured and end use is considered

The Use of in vitro Models for Mechanistic Studies in Toxicology.

Two areas of current interest in toxicology have been studied using in vitro models. 1. Carcinogen-induced nuclear enlargement has been reported both in vitro and in vivo, but the mechanism, and whether it is causally related to carcinogenesis, has not yet been established. In order to obtain some insight into potential mechanisms, several cell culture systems were used to investigate the role of increased DNA content in induction of nuclear enlargement. N-methyl-N-nitrosourea and adriamycin were shown to induce nuclear enlargement in vitro following ‘pulse’ treatment. This was accompanied by an increase in the proportions of cells in the G2+M phase of the cell cycle, possibly due to G2 block. There was some evidence of polyploidy induction following adriamycin treatment, but not following N-methyl-N-nitrosourea treatment. In contrast, diethylstilboestrol increased the range of nuclear areas and DNA content, to both less than and greater than that of control cells, but only after a prolonged exposure period of 48h. These data were consistent with diethylstilboestrol inducing spindle damage. 2. In vitro models were also used to investigate steatogen-induced hepatotoxicity and hepatotoxicity induced by fibrinogen receptor antagonists. The need to include toxicity markers in in vitro hepatotoxicity tests which are relevant to the type of in vivo hepatotoxicity was investigated. In both cases, simple cytotoxicity markers were used in combination with more sensitive biochemical or morphological markers. In the case of steatogen-induced hepatotoxicity it was found that measurement of intracellular triglyceride levels provided more information on the in vitro toxicity of ethanol and valproic acid than measurement of simple cytotoxicity. However, the inclusion of triglyceride measurement did not provide additional information on the in vitro toxicity of ethionine. It was also found that in vitro examination of mitochondrial changes following treatment of hepatocytes with fibrinogen receptor antagonists was a more sensitive marker than simple cytotoxicity markers

The John W. Anderson Slave Pen

At the end of 18th century America, a series ofevents occurred that forever changed the economic and political status of white Americans. These changes were heavily influenced by the transportation of blacks to this country, the circumstances surrounding their enslavement, and the increasing demand for cotton. America\u27s founders prohibited the importation of enslaved Africans into the United States at the 1787 Constitutional Convention. This prohibition, however, occurred at a time when America was expanding and additional labor was necessary. The invention of the cotton gin in 1793 increased the amount of market ready cotton. The Louisiana Purchase doubled the size of the United States, which meant more fertile soil for cotton production via slave labor. These major changes in the American economy meant that white Americans had to continue slave operations in a way that complied with the prohibition against importing slaves

The John W. Anderson Slave Pen

At the end of 18th century America, a series ofevents occurred that forever changed the economic and political status of white Americans. These changes were heavily influenced by the transportation of blacks to this country, the circumstances surrounding their enslavement, and the increasing demand for cotton. America\u27s founders prohibited the importation of enslaved Africans into the United States at the 1787 Constitutional Convention. This prohibition, however, occurred at a time when America was expanding and additional labor was necessary. The invention of the cotton gin in 1793 increased the amount of market ready cotton. The Louisiana Purchase doubled the size of the United States, which meant more fertile soil for cotton production via slave labor. These major changes in the American economy meant that white Americans had to continue slave operations in a way that complied with the prohibition against importing slaves

Garner Courage

Robert Garner was born into a slave family on the James Marshall plantation located in Richwood, Kentucky. At 25 years old, Robert executed a plan to free all eight members of his family. They were captured in Cincinnati. His wife, Margaret, determined not to return to slavery, sought to kill her children and then herself. She was able to kill her youngest daughter by slitting her throat. The group members that remained alive were turned over to the U.S. Marshal of Cincinnati for violating the 1850 Fugitive Slave Act. Knowledge of the Gamers\u27 story and their gruesome capture outraged the Black community in Cincinnati, OH. The Garner trial became one of the longest fugitive slave trials in history. In an interview with The Cincinnati Chronicle, Robert Garner proudly talked of the new life he had started to build. From been convicted in a federal hearing of violating the 1850 Fugitive Slave Act, surviving enslavement in Mississippi and the death of his wife, to joining the armed forces; he presented himself to the reporter as a man who had known enslavement, yet he, like those who had influenced him, was not broken

The John W. Anderson Slave Pen

At the end of 18th century America, a series ofevents occurred that forever changed the economic and political status of white Americans. These changes were heavily influenced by the transportation of blacks to this country, the circumstances surrounding their enslavement, and the increasing demand for cotton. America\u27s founders prohibited the importation of enslaved Africans into the United States at the 1787 Constitutional Convention. This prohibition, however, occurred at a time when America was expanding and additional labor was necessary. The invention of the cotton gin in 1793 increased the amount of market ready cotton. The Louisiana Purchase doubled the size of the United States, which meant more fertile soil for cotton production via slave labor. These major changes in the American economy meant that white Americans had to continue slave operations in a way that complied with the prohibition against importing slaves