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Animals are still widely used in drug development and safety tests, despite evidence for their lack of predictive value. In this regard, we recently showed, by producing Likelihood Ratios (LRs) for an extensive data set of over 3,000 drugs with both animal and human data, that the absence of toxicity in animals provides little or virtually no evidential weight that adverse drug reactions will also be absent in humans. While our analyses suggest that the presence of toxicity in one species may sometimes add evidential weight for risk of toxicity in another, the LRs are extremely inconsistent, varying substantially for different classes of drugs. Here, we present further data from analyses of other species pairs, including nonhuman primates (NHPs), which support our previous conclusions, and also show in particular that test results inferring an absence of toxicity in one species provide no evidential weight with regard to toxicity in any other species, even when data from NHPs and humans are compared. Our results for species including humans, NHPs, dogs, mice, rabbits, and rats, have major implications for the value of animal tests in predicting human toxicity, and demand that human-focused alternative methods are adopted in their place as a matter of urgency.

We are in total agreement with the ABPI that “informed debate amongst key stakeholders” is important. However, this should include animal protection groups, in addition to their suggested partnership between “the pharmaceutical industry, academia and the regulatory authorities.”Unfortunately, as we have tried to explain, we believe that the ABPI authors have been too eager to play down the importance of our study. Far from being constructive, their critique is overly critical to the point of being unhelpful. Criticism must be fair and robust. When it has a weak scientific basis, it is unacceptable, especially when it is used as a basis to persist with the status quo, for which there is weak supportive evidence.We acknowledge (as we did in our paper) that there are inherent and unavoidable caveats to our analysis. Notwithstanding this, our study is unprecedented in scale and type. Notably, it is much broader and more comprehensive than any of the studies cited by the ABPI, which involved a combination of: more limited (smaller and more restricted) sample sizes; exaggeration in terms of their supportive nature for dog studies; overlooking of evidence against dog studies; incomplete statistics, from which conclusions could not be drawn; incorrect statistical definitions and analyses; and questionable, or absent, human relevance. Conspicuously, none of these studies addressed any of the criticisms made by the ABPI of our study, on dosage and rare events, for example. In addition, the ABPI failed to provide constructive suggestions on howwe could go about addressing these concerns. How does the ABPI suggest we address the problems of data limitations, dosage/exposure, and incidence of toxicity — considerations absent, or at least almost absent, in previous studies? Constructive criticism must include suggestions on how to go about resolving those issues. Arguably, given the restricted amount of data that are publicly available, at least some of those concerns cannot be addressed by third parties. The ABPI, and associated groups, could (and should) help by facilitating access to such information. Nevertheless, we were already in the process of analysing the data available to us in greater depth, the outcome of which will be published in the near future.To reiterate: we did all we could do, with the data that were available to us, to produce a study of unprecedented scale and type. We are confident about, and as certain as we could be of, our analysis and our conclusions. They should not be overlooked because of their source, and because they are inconvenient to any stakeholders (including the Federation of Laboratory Animal Breeders Associations, which, not surprisingly, supports the ABPI's arguments). Should the ABPI be genuinely concerned that our analysis, using all the data and correct statistical methods at our disposal, is not sufficient, we refer it to our statement within our paper: “…if any pharmaceutical industry stakeholders have issues or concerns with our conclusions, we would encourage them to conduct further analyses by using their own proprietary data, and/or to facilitate such investigations by making available anonymised data, in accordance with the promotion of transparency encouraged by EU Directive 2010/63/EU, as well as to engage fully in constructive discussion and debate with us and our colleagues in animal protection organisations.” The only acceptable response by industry and regulators should be, at the very least, a desire for positive action to facilitate, or conduct, if possible, another study on a greater scale, involving the use of proprietary data. To ignore the most relevant findings, and/or focus on other inferred shortcomings of other elements of the study, is unacceptable, particularly when the upshot is to defend and perpetuate seriously flawed dog toxicology, with little or no substantiation.

Activating transcription factor 2 (ATF2), a ubiquitously expressed member of the basic region leucine zipper (bZIP) family of transcription factors activated by mitogen activated protein kinase (MAPK) pathways, is important in the mediation of cellular stress responses, development and transformation. We have previously reported the differential expression of active ATF2 in the human myometrium throughout pregnancy and labour, and identified and partially characterized a novel splice variant ATF2-small (ATF2-sm). To further understand the role of these factors in the myometrium, we have used gene microarrays to define the target genes in cultured myometrial cells stably-transfected with ATF2 and ATF2-sm cDNAs. Many of the genes identified appear to have potential roles in regulating myometrial function and include proteins involved in G-protein receptor signalling, cytokine signalling, transcriptional regulation, cell-cycle control, formation of the extracellular matrix and cytoskeletal architecture. ATF2 was found to affect the expression of 204 genes; 113 being up-regulated and 91 down-regulated whereas the novel ATF2-sm factor altered the expression of 55 genes; expression was increased in 29 cases and decreased in 26. A further 25 genes affected by ATF2-sm were identified by suppression subtractive hybridisation (SSH). Notably, the genes affected by ATF2 and ATF2-sm appear to belong to discrete groups: only two genes were affected by both factors.

cAMP-response element (CRE) binding (CREB) and modulator (CREM) proteins, activated by protein kinase A-mediated phosphorylation, bind as homo- and heterodimers to promoters containing CRE and activator protein 1 (AP-1) sites to alter target-gene expression. We have previously reported differential expression of CREB and CREM splice variants CREMα and CREMτ2α in human myometrium during pregnancy and labour. Via microarray studies with cultured myometrial cells stably transfected with CREB, CREMα and CREMτ2α cDNAs, CREB affected the expression of 958 genes; 522 being up-regulated and 436 down-regulated. CREMα altered the expression of 118 genes; 71 were increased and 47 decreased. CREMτ2α affected 220 genes; 148 were activated and 72 repressed. Notably, genes affected by CREB, CREMα and CREMτ2α belong to largely discrete groups: less than 9% were affected by more than one factor. Genes involved in regulation of cell death and apoptosis, growth and maintenance, signal transduction, physiological and developmental processes, protein kinase cascades, extracellular matrix, cytoskeleton, cell-cycle regulation, transport, and a variety of enzymes, intracellular components and nucleic acid-binding proteins have been described, many of which are involved in the modulation of myometrial activity during pregnancy and parturition.

Examines the testing of chemicals on pregnant animals in an effort to determine how the substances may be for humans. Details of the case of thalidomide; Examples of the discordance found in teratology; Information on the Embryonic Stem Cell Test. INSET: Help Us Reform America's Largest Birth Defects Charity.