ATLA 34, 2006

/ATLA 34, 2006

Comment – Four papers on the OECD Health Effects Test Guidelines

Michael Balls and Robert D. Combes
Angela Auletta
John E. Doe, Richard W. Lewis and Philip A. Botham
Barry Phillips


This post combines four papers:
The OECD Health Effects Test Guidelines: A Challenge to the Sincerity of Commitment to the Three Rs by Michael Balls and Robert D. Combes
An Assessment of Some Recommendations Made Concerning the OECD Health Effects Test Guidelines by Angela Auletta
Comments on A Scientific and Animal Welfare Assessment of the OECD Health Effects Test Guidelines for the Safety Testing of Chemicals Under the European Union REACH System by John E. Doe, Richard W. Lewis and Philip A. Botham
OECD Test Guidelines are Tools, not Blueprints, for Chemical Safety Assessment by Barry Phillips

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Applying the Three Rs to Animal Experimentation and Animal Testing: Are We Merely Drifting or Lying at Anchor?

Michael Balls and Robert Combes

This issue of ATLA (34 [1], 2006) contains a number of very important items, which can be seen as encouraging or discouraging, depending on one’s hopes and ambitions with respect to alternatives.
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News & Views

ATLA Staff Writer

Avian Flu Vaccines
Fried Eggs and Green Ham? — Transgenic Pigs
EU Action Plan on Animal Welfare
Extension of the US Chimpanzee Breeding Moratorium
Der Drei R
Hybrid Rabbit–Human Embryonic Stem Cells
Scandal over Faked Cloning Research
Call for Alternative Proposals
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2017-01-09T06:36:22+00:00 Tags: |

ECVAM News & Views

ATLA Staff Writer

Europe Goes Alternative
ECVAM Task Forces and Related Activities
Publication of a Study Report on the Optimisation of In Vitro Models for Studies on Intestinal Barrier Functions
ESAC Peer Review on the Micronucleus Test In VitroPublications
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2017-01-09T06:36:23+00:00 Tags: |

Introduction to the Seventh Annual FRAME Lecture, the First Bill Annett Lecture, Presented by Dr Julia Fentem at the Kennel Club, London, on 19 October 2005

Julia H. Fentem

Bill Annett was involved in public relations throughout his professional life, and after his “retirement”, served as a FRAME consultant for 26 years. He died suddenly, on 9 November 2004, whilst still in active service at the age of 92. The FRAME Trustees have decided to rename the FRAME Annual Lecture in his memory, and it is particularly appropriate that Dr Julia Fentem, the Seventh FRAME Annual Lecturer, should be with us today to give the First Bill Annett Lecture.
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Animal Carcinogenicity Studies: 1. Poor Human Predictivity

Andrew Knight, Jarrod Bailey and Jonathan Balcombe

The regulation of human exposure to potentially carcinogenic chemicals constitutes society’s most important use of animal carcinogenicity data. Environmental contaminants of greatest concern within the USA are listed in the Environmental Protection Agency’s (EPA’s) Integrated Risk Information System (IRIS) chemicals database. However, of the 160 IRIS chemicals lacking even limited human exposure data but possessing animal data that had received a human carcinogenicity assessment by 1 January 2004, we found that in most cases (58.1%; 93/160), the EPA considered animal carcinogenicity data inadequate to support a classification of probable human carcinogen or non-carcinogen. For the 128 chemicals with human or animal data also assessed by the World Health Organisation’s International Agency for Research on Cancer (IARC), human carcinogenicity classifications were compatible with EPA classifications only for those 17 having at least limited human data (p = 0.5896). For those 111 primarily reliant on animal data, the EPA was much more likely than the IARC to assign carcinogenicity classifications indicative of greater human risk (p < 0.0001). The IARC is a leading international authority on carcinogenicity assessments, and its significantly different human carcinogenicity classifications of identical chemicals indicate that: 1) in the absence of significant human data, the EPA is over-reliant on animal carcinogenicity data; 2) as a result, the EPA tends to over-predict carcinogenic risk; and 3) the true predictivity for human carcinogenicity of animal data is even poorer than is indicated by EPA figures alone. The EPA policy of erroneously assuming that tumours in animals are indicative of human carcinogenicity is implicated as a primary cause of these errors.
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Animal Carcinogenicity Studies: 2. Obstacles to Extrapolation of Data to Humans

Andrew Knight, Jarrod Bailey and Jonathan Balcombe

Due to limited human exposure data, risk classification and the consequent regulation of exposure to potential carcinogens has conventionally relied mainly upon animal tests. However, several investigations have revealed animal carcinogenicity data to be lacking in human predictivity. To investigate the reasons for this, we surveyed 160 chemicals possessing animal but not human exposure data within the US Environmental Protection Agency chemicals database, but which had received human carcinogenicity assessments by 1 January 2004. We discovered the use of a wide variety of species, with rodents predominating, and of a wide variety of routes of administration, and that there were effects on a particularly wide variety of organ systems. The likely causes of the poor human predictivity of rodent carcinogenicity bioassays include: 1) the profound discordance of bioassay results between rodent species, strains and genders, and further, between rodents and human beings; 2) the variable, yet substantial, stresses caused by handling and restraint, and the stressful routes of administration common to carcinogenicity bioassays, and their effects on hormonal regulation, immune status and predisposition to carcinogenesis; 3) differences in rates of absorption and transport mechanisms between test routes of administration and other important human routes of exposure; 4) the considerable variability of organ systems in response to carcinogenic insults, both between and within species; and 5) the predisposition of chronic high dose bioassays toward false positive results, due to the overwhelming of physiological defences, and the unnatural elevation of cell division rates during ad libitum feeding studies. Such factors render profoundly difficult any attempts to accurately extrapolate human carcinogenic hazards from animal data.
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Animal Carcinogenicity Studies: 3. Alternatives to the Bioassay

Andrew Knight, Jarrod Bailey and Jonathan Balcombe

Conventional animal carcinogenicity tests take around three years to design, conduct and interpret. Consequently, only a tiny fraction of the thousands of industrial chemicals currently in use have been tested for carcinogenicity. Despite the costs of hundreds of millions of dollars and millions of skilled personnel hours, as well as millions of animal lives, several investigations have revealed that animal carcinogenicity data lack human specificity (i.e. the ability to identify human non-carcinogens), which severely limits the human predictivity of the bioassay. This is due to the scientific inadequacies of many carcinogenicity bioassays, and numerous serious biological obstacles, which render profoundly difficult any attempts to accurately extrapolate animal data in order to predict carcinogenic hazards to humans. Proposed modifications to the conventional bioassays have included the elimination of mice as a second species, and the use of genetically-altered or neonatal mice, decreased study durations, initiation–promotion models, the greater incorporation of toxicokinetic and toxicodynamic assessments, structure-activity relationship (computerised) systems, in vitro assays, cDNA microarrays for detecting changes in gene expression, limited human clinical trials, and epidemiological research. The potential advantages of nonanimal assays when compared to bioassays include the superior human specificity of the results, substantially reduced time-frames, and greatly reduced demands on financial, personnel and animal resources. Inexplicably, however, the regulatory agencies have been frustratingly slow to adopt alternative protocols. In order to decrease the enormous cost of cancer to society, a substantial redirection of resources away from excessively slow and resource-intensive rodent bioassays, into the further development and implementation of non-animal assays, is both strongly justified and urgently required.
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Metabolism: A Bottleneck in In Vitro Toxicological Test Development

Sandra Coecke, Hans Ahr, Bas J. Blaauboer, Susanne Bremer, Silvia Casati, Josè Castell, Robert Combes, Raffaella Corvi, Charles L. Crespi, Michael L. Cunningham, Greetje Elaut, Brighitta Eletti, Andreas Freidig, Alessandra Gennari, Jean-François Ghersi-Egea, Andre Guillouzo, Thomas Hartung, Peter Hoet, Magnus Ingelman-Sundberg, Sharon Munn, Walter Janssens, Bernhard Ladstetter, David Leahy, Anthony Long, Annarita Meneguz, Mario Monshouwer, Siegfried Morath, Fred Nagelkerke, Olavi Pelkonen, Jessica Ponti, Pilar Prieto, Lysianne Richert, Enrico Sabbioni, Beatrice Schaack, Winfried Steiling, Emanuela Testai, Joan-Albert Vericat and Andrew Worth

This is the 54th report of a series of workshops organised by the European Centre for the Validation of Alternative Methods (ECVAM). The main objective of ECVAM, as defined in 1993 by its Scientific Advisory Committee, is to promote the scientific and regulatory acceptance of alternative methods which are of importance to the biosciences, and which reduce, refine or replace the use of laboratory animals.
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